Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters

ABSTRACT

Disclosed are bioavailable solid state (17-β)-Hydroxy-4-Androsten-3-one esters suitable for pharmaceutical uses and administration to mammals in need of (17-β)-Hydroxy-4-Androsten-3-one.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. patent application Ser. No.14/839,820, filed Aug. 28, 2015, which claims the benefit U.S.Provisional Application Ser. No. 62/043,337, filed Aug. 28, 2014, whichare incorporated herein by reference in its entirety.

FIELD

Disclosed herein are solid state (17-β)-Hydroxy-4-Androsten-3-one esterssuitable for pharmaceutical uses and administration to mammals (e.g.,humans) in need of (17-β)-Hydroxy-4-Androsten-3-one.

BACKGROUND

Different solid state forms of an ester of an active pharmaceuticalingredient (API) or esterified active pharmaceutical ingredient (EAPI)may possess different properties that can provide a formulation, inwhich the EAPI is included, with specific advantages, for example, byfacilitating better processing or handling characteristics, changing thedissolution profile in a favorable direction, or improving stability(polymorph as well as chemical stability) and shelf-life. Thesevariations in the properties of different solid state forms may alsotranslate to benefits to a final dosage form, for instance, by providingor contributing to improved bioavailability. Different solid state formsof an EAPI may also give rise to a variety of polymorphs or crystallineforms, which may in turn provide additional opportunities to assessvariations in the properties and characteristics of a solid EAPI.

An important characteristic of EAPI is that it's dissolution or releaserate does not change substantially over time. Changes in dissolution orrelease rate of EAPI over time can result in otherwise identicalproducts except for the solid state form (e.g., having the same EAPI,formulations components and amounts thereof), but differentpharmacokinetic properties which can change or alter the efficacy orsafety of a drug product.

The stability of EAPI in pharmaceutical preparations (e.g., compositionsand unit dosage forms) is also important. For example, if the EAPIchanges physical form (e.g., crystal form or amount thereof) in apharmaceutical composition or unit dosage form, this can also affectpharmacokinetic properties and therefore related safety and efficacyparameters.

To be useful, the solid state has to be stable. A number of examples ofbulk drug substance and pharmaceutical compositions/dosage forms thathave changed physical form are known in the literature and have resultedin substantial problems to patients receiving these drugs. A well knownexample is ritonavir which underwent a change in crystal form resultingin the product failing dissolution tests and being pulled off the marketfor a period of time (see Morissette et al. Proc Natl Acad Sci USA. 2003Mar. 4; 100(5):2180-4). Other high profile cases include the recall ofbatches of Neupro (rotigotine) due to the appearance of a new polymorphin 2008, recall of 1.5 million tablets of warfarin in 2010 due toconcerns over 2-propanol levels, which potentially could affect APIcrystallinity, and in 2010 the recall of 60 million tablets of Avalideover concerns in variability in the amounts of the less solublepolymorph of irbesartan in 2010. See Lee et al. Annu. Rev. Chem. Biomol.Eng. 2011, 2, 259-280.

Absorption of any prodrug such as an ester derivative of an API (EAPI)needs to be managed to provide adequate and sustained levels of the APIderived from EAPI in vivo without adding any safety issues associatedwith the ester or its metabolite. Solubility, release, dissolution andpartitioning of EAPI in a particular solvent is a function oflipophilicity and is related to solid state characteristics e.g., thephysical form of the drug substance such as crystal form, solvation,whether or not amorphous material is present, etc. Therefore, the solidstate physical form is one of the key properties with respect to ease ofmanufacturing, storage, and performance of the EAPI for enabling safeand effective levels of API.

Esters of (17-β)-Hydroxy-4-Androsten-3-one, which themselves are notthought to be biological active, are known to be transformed to thebiologically active molecule ((17-β)-Hydroxy-4-Androsten-3-one in vivo(and other related metabolites like (17-β)-Hydroxy-5α-androstan-3-one)and therefore can be used for treating patients in need of(17-β)-Hydroxy-4-Androsten-3-one treatment. However, inadequatesolubility and/or release or dissolution or partitioning and/or physicalstability of the solid state of the EAPI can result in poorbioavailability of (17-β)-Hydroxy-4-Androsten-3-one, a useful hormonefor the treatment of several disease states such as male or femalehypogonadism.

Several prodrug esters of (17-β)-Hydroxy-4-Androsten-3-one have beenreported in the literature (Gooren L J Front Horm Res. 2009; 37:32-5).However, in addition to overcoming solubility challenges with(17-β)-Hydroxy-4-Androsten-3-one esters, adequate absorption andconversion rate into the parent drug remain an important design elementin preparing and identifying solid state esters of(17-β)-Hydroxy-4-Androsten-3-one. Approaches to date have failed todisclose or adequately characterize specific solid state(17-β)-Hydroxy-4-Androsten-3-one esters (i.e., the tridecanoate,tetradecanoate esters, and others), compositions and dosage forms havingthese esters and methods of their use that would be particularly usefulin overcoming poor solubility in biologically relevant media such asaqueous media for adequate release/dissolution of the(17-β)-Hydroxy-4-Androsten-3-one ester or in lipophilic additives suchas fatty acids or fatty acid glycerides for adequatelipid/membrane/chylomicron partitioning.

Steroids including steroid esters, testosterone and testosterone estersare known to exhibit different solid sate forms that have differentproperties including dissolution, bioavailability and absorption (Seee.g., Ballard B E, Biles J, Steroids, 1964; 4: 273; Bouche R,Draguet-Brughmans M, J Pharm Belg, 1977; 32: 347; Carless et al. Journalof Pharmacy and Pharmacology Volume 20, Issue 8, pages 630-638, August1968; Borka & Haleblian (1990) Acta Pharm. Jugosl. 40:71-94).

There is a need for stable and bioavailable solid state forms of esters(17-β)-Hydroxy-4-Androsten-3-one such as (17-β)-3-Oxoandrost-4-en-17-yltridecanoate (or the corresponding tetradecanoate) that would besuitable for use in treatment of subjects in need of(17-β)-Hydroxy-4-Androsten-3-one.

SUMMARY OF THE INVENTION

Solid state forms of (17-β)-Hydroxy-4-Androsten 3-one esters areprovided herein. In particular, new solid state forms of medium and longchain alkyl esters of (17-β)-Hydroxy-4-Androsten-3-one are provided. Inspecific aspects, the ester of (17-β)-Hydroxy-4-Androsten-3-one is solidstate (17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate.

We have found that not all solid state forms of the tridecanoate esterderivative of ((17-β)-Hydroxy-4-Androsten-3-one are alike and suitablefor treatment of mammals in need of (17-β)-Hydroxy-4-Androsten-3-one. Wehave found that specific solid state tridecanoate ester derivatives of(17-β)-Hydroxy-4-Androsten-3-one wherein at least 0.001% (e.g., at least0.01, 0.1 1.0 or 10%) of the solid state active tridecanoate esterderivative of (17-β)-Hydroxy-4-Androsten-3-one dissolves in 1000 mL 8%Triton X100 containing aqueous solution in 30 minutes in a USP Type 2apparatus at 37° C. at 100 r.p.m. are more suitable for administering toa human (e.g., treating or preventing a disease, condition or disorder).

Additionally, we have now found that the apparent solubility of onlyspecific solid state forms of ((17-β)-Hydroxy-4-Androsten-3-one estersin lipophilic additives, such as a fatty acid (e.g. oleic acid) or fattyacid glycerides (mono, di or triglceride or mixtures thereof), of atleast about 5 mg/g or at least about 100 mg/g facilitates adequatepartitioning into the formulation or physiologically generatedchylomicrons, thus enhancing their effective oral bioavailability. Thus,adequate solubility of specific solid state forms(17-β)-Hydroxy-4-Androsten-3-one esters in lipids or lipophilicadditives (e.g., at least 5 mg/g or at least 100 mg/g) is desired foreffective oral absorption. Without wishing to be bound by theory it isbelieved that excessive lipid solubility in lipophilic additives such asmedium/long chain fatty acids and food glycerides (or chemical modifiedfood glycerides), such as greater than 300 mg/g, may not causesufficient partitioning of the drug substance out of chylomicrons, andthus not be adequately bioavailable. Therefore, in one embodiment, solidstate forms of an ester of (17-β)-Hydroxy-4-Androsten-3-one such as thetridecanoate ester, which has an apparent solubility in a lipid additiveof at least about 5 mg/g to at least about 100 mg/g are provided whichis useful for treating mammals (e.g., humans) in need of(17-β)-Hydroxy-4-Androsten-3-one treatment.

Moreover, it has been found that therapeutic utility of solid stateforms of the ester derivatives of this invention are dissolution/releasedependent in aqueous medium; therefore, in one embodiment the solidstate tridecanoate ester derivative of (17-β)-Hydroxy-4-Androsten-3-oneis provided, wherein at least 20% more (17-β)-3-Oxoandrost-4-en-17-yltridecanoate is released using a USP type 2 apparatus in about 1000 mL8% Triton X100 solution in water, at 30 minutes than an equivalentamount of solid state active tridecanoate ester derivative of(17-β)-Hydroxy-4-Androsten-3-one that dissolves less than 0.001% in 8%Triton X100 at 30 minutes.

It was found that compositions of select solid forms described hereinare adequately bioavailable. In one embodiment, a composition foradministration to a human subject in need of((17-β)-Hydroxy-4-Androsten-3-one therapy is provided, the compositioncomprising or made from: a) a solid state of a(17-β)-Hydroxy-4-Androsten-3-one ester and b) a pharmaceuticallyacceptable carrier, wherein upon oral administration of the solid stateof an ester of (17-β)-Hydroxy-4-Androsten-3-one to the human subject, atleast about 0.1% 0.5%, 1%, 2%, or 3% of the(17-β)-Hydroxy-4-Androsten-3-one equivalent dose is bioavailable(17-β)-Hydroxy-4-Androsten-3-one to the human subject.

Thus, in one embodiment, a solid state EAPI which is(17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate is provided. The solidstate EAPI is crystalline, non-crystalline, or a mixture thereof. Forexample, the solid state EAPI is crystalline(17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. In another example, thesolid state EAPI is non-crystalline (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. In a specific aspect, thesolid state EAPI is amorphous (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. The solid state EAPI isuseful for administration to a human e.g., the solid state EAPI is(17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate useful for administrationto humans.

Solid state EAPI is provided herein which is crystalline(17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. The crystalline solidstate EAPI can be a particular crystal form, a solvate of a crystalform, a polymorph, a pseudopolymorph, a pharmaceutically acceptablesolvate, or a hydrate of crystalline (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. In a specific aspect, thecrystalline solid state EAPI is a crystal form substantially free ofother crystal forms of solid state EAPI. In another specific aspect, thecrystalline EAPI is substantially free of amorphous solid state EAPI.

In a related aspect, amorphous solid state EAPI is provided which issubstantially free of crystalline EAPI.

Solid state EAPI is provided herein having a particular sizecharacteristic. For example provided herein is solid state EAPI which isnot-milled or is milled, micronized or nanosized. Thus, solid state EAPIis provided which is (17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate where the EAPI isnot-milled or is milled, micronized or nanosized. In specific aspects,the solid state EAPI is (17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate wherein the particle sizeof the EAPI is less than 200 nm (“nanometer”), from 200 to 500 nm, from500 to 1000 nm, from 1 to 50 μm (“micrometer”), from 50 to 250 μm, from250 to 500 μm, from 500 to 1000 μm, or greater than 1000 μm. In anotheraspect, the solid state EAPI is (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate having ads) of greaterthan 1000 μm, from 355 to 1000 μm, from 180 to 355 μm, from 125 to 180μm, 90 to 125 μm 1 to 90 μm, or less than 1 μm. In another relatedaspect, the solid state EAPI is (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate having a D₁₀, D₅₀, or D₉₀that is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from1 to 50 μm, from 50 to 250 μm, from 250 to 500 μm, from 500 to 1000 μm,or greater than 1000 μm. In one particular aspect, the EAPI having aparticular size or size characteristics is crystalline EAPI. In anotherparticular aspect, the EAPI having a particular size or sizecharacteristics is a crystal form of the EAPI substantially free ofother crystal forms of the EAPI. In yet another, the EAPI having aparticular size or size characteristics is amorphous EAPI. In yetanother, the EAPI having a particular size or size characteristics isamorphous EAPI substantially free of crystalline EAPI.

Pharmaceutical compositions are provided herein having or prepared froma solid state EAPI as described in the paragraphs above. For example,the pharmaceutical composition is prepared from or has a solid stateEAPI chosen from (17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, and(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate and one or morepharmaceutically acceptable excipients or carriers. The pharmaceuticalcomposition described herein can comprise or be prepared fromcrystalline solid state EAPI, amorphous solid state EAPI, or acombination thereof. The pharmaceutical composition comprises or isprepared from a particular crystal form, a solvate of a crystal form, apolymorph, a pseudopolymorph, a pharmaceutically acceptable solvate, ora hydrate of crystalline (17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. Alternatively, thepharmaceutical composition is prepared from or comprises amorphous solidstate (17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. In some aspects, thepharmaceutical composition comprises or is prepared from solid stateEAPI which is (17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate where the EAPI isnot-milled or is milled, micronized or nanosized. Is specific aspects,the pharmaceutical composition comprises or is prepared from solid stateEAPI is which is (17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yldodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate wherein the particle sizeof the EAPI is less than 200 nm, from 200 to 500 nm, from 500 to 1000nm, from 1 to 50 μm, from 50 μm to 250 μm, from 250 μm to 500 μm, from500 μm to 1000 μm, or greater than 1000 μm. In another aspect, thepharmaceutical composition comprises or is prepared from solid stateEAPI is which is (17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate having a d₅₀ of greaterthan 1000 μm, from 355 to 1000 μm, from 180 to 355 μm, from 125 to 180μm, from 90 to 125 μm, from 1 to 90 μm, or less than 1 μm. In anotherrelated aspect, the pharmaceutical composition comprises or is preparedfrom solid state EAPI is which is (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate having a D₁₀, D₅₀, or D₉₀that is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from1 to 50 μm, from 50 to 250 μm, from 250 to 500 μm, from 500 to 1000 μm,or greater than 1000 μm. In some specific aspects, the pharmaceuticalcomposition of this paragraph is formulated for topical, enteral orparenteral administration. In some aspects, the pharmaceuticalcomposition of this paragraph is formulated for buccal, sublingual, orsublabial administration. In some specific aspects, the pharmaceuticalcomposition of this paragraph is formulated for nasal, rectal or vaginaladministration. In some specific aspects, the pharmaceutical compositionof this paragraph is formulated for intravenous, subcutaneous,intramuscular, intradermal, intraspinal, intrathecal, or intra-arterialadministration. In some specific aspects, the pharmaceutical compositionof this paragraph is formulated as a liquid, solution, suspension,dispersion, solid, semi-solid, a gel, a lotion, paste, foam, spray,suspension, dispersion, syrup, or ointment. In some specific aspects,the pharmaceutical composition of this paragraph is formulated as atincture, patch, injectable, or oral dosage form. In some aspects, thepharmaceutical composition of this paragraph comprises solubilized orpartially solubilized (17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate solid state EAPI. In oneaspect, the pharmaceutical composition or unit dosage forms is suitablefor oral administration (e.g., capsule or tablet).

Provided herein are unit dosage form comprising or prepared from thesolid state EAPI or pharmaceutically compositions as described in theparagraphs above.

Additionally, described herein are methods of making solid state EAPIand methods of using solid state EAPI.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A shows a non-limiting example of a synthetic scheme for makingsolid state form (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate disclosedin this invention.

FIG. 1B shows non-limiting examples of methods for crystallizing solidstate forms of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate disclosedherein.

FIG. 2 shows a differential scanning calorimetry first heat cycle plotfor a solid state form of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate asdisclosed herein.

FIG. 3 shows a differential scanning calorimetry first cool cycle, plotfor a solid state form of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate asdisclosed herein.

FIG. 4 shows a differential second heat cycle plot for a solid stateform of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate as disclosed herein.

FIG. 5 shows a differential scanning calorimetry second cool cycle plotfor a solid state form of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate asdisclosed herein.

FIG. 6 shows a plot of a powder x-ray diffraction analysis of a solidstate form of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate as disclosedherein.

FIG. 7 shows the release profile stability of a pharmaceuticalcomposition having or prepared from (17-β)-3-Oxoandrost-4-en-17-yltridecanoate. See Example 10.

FIG. 8 shows the file stability of a pharmaceutical composition havingor prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. SeeExample 10.

DETAILED DESCRIPTION OF THE INVENTION

The specific solid state forms of (17-β)-Hydroxy-4-Androsten-3-oneesters disclosed herein have one or more advantageous propertiescompared to other forms such as chemical or polymorphic purity,increased crystallinity, flowability, solubility, dissolution rate,bioavailability, morphology or crystal habit, specific surface andpycnometric density, bulk/tap density, stability (e.g., such as chemicalstability as well as thermal and mechanical stability with respect topolymorphic conversion), stability towards hydration and/or storagestability, a lower degree of hygroscopicity, low content of residualsolvents and advantageous processing and handling characteristics suchas compressibility and bulk density. Specific solid state forms of(17-β)-Hydroxy-4-Androsten-3-one esters are provided herein. New solidstate forms of medium and long chain alkyl esters of(17-β)-Hydroxy-4-Androsten-3-one are provided, particularly(17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate.

It should be noted that, the singular forms “a,” “an,” and, “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to “an excipient” includes reference to oneor more of such excipients, and reference to “a carrier” includesreference to one or more of such carriers.

The term “API” refers to active pharmaceutical ingredient or drug andmeans (17-β)-Hydroxy-4-Androsten-3-one (also known as testosterone)which is considered the biologically active agent for the purpose ofthis disclosure. It is noted that (17-β)-Hydroxy-4-Androsten-3-one canbe converted in vivo to (17-β)-hydroxy-5α-androstan-3-one (directly orvia the corresponding ester) which is also biological activity as wellas other metabolites. The term “EAPI” means an ester of(17-β)-Hydroxy-4-Androsten-3-one, a prodrug of the biologically activeagent. It is understood that the EAPI can also have biological activitywithout cleavage of the ester, but for the purpose of this invention theAPI is considered the pharmacological agent.

Concentrations, amounts, levels and other numerical data may beexpressed or presented herein in a range format. It is to be understoodthat such a range format is used merely for convenience and brevity andthus should be interpreted flexibly to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges or decimalunits encompassed within that range as if each numerical value andsub-range is explicitly recited. As an illustration, a numerical rangeof “about 1 to about 5” should be interpreted to include not only theexplicitly recited values of about 1 to about 5, but also includeindividual values and sub-ranges within the indicated range. Thus,included in this numerical range are individual values such as 2, 3, and4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as wellas 1, 2, 3, 4, and 5, individually. This same principle applies toranges reciting only one numerical value as a minimum or a maximum.Furthermore, such an interpretation should apply regardless of thebreadth of the range or the characteristics being described.

In this specification, “comprises,” “comprising,” “containing” and“having” and the like can have the meaning ascribed to them in U.S.patent law and can mean “includes,” “including,” and the like, and aregenerally interpreted to be open ended terms. The terms “consisting of”or “consists of” are closed terms, and include only the components,structures, steps, or the like specifically listed in conjunction withsuch terms, as well as that which is in accordance with U.S. patent law.“Consisting essentially of” or “consists essentially of” have themeaning generally ascribed to them by U.S. patent law. In particular,such terms are generally closed terms, with the exception of allowinginclusion of additional items, materials, components, steps, orelements, that do not materially affect the basic and novelcharacteristics or function of the item(s) used in connection therewith.For example, trace elements present in a composition, but not affectingthe compositions nature or characteristics would be permissible ifpresent under the “consisting essentially of” language, even though notexpressly recited in a list of items following such terminology. Whenusing an open ended term in the specification, like “comprising” or“including,” it is understood that direct support should be affordedalso to “consisting essentially of” language as well as “consisting of”language as if stated explicitly and vice versa.

The terms “serum testosterone” or “serum(17-β)-Hydroxy-4-Androsten-3-one levels,” “serum T levels,” “serumtestosterone concentration,” “plasma testosterone concentration,”“testosterone concentration in the blood,” and “serum testosteroneconcentration,” are used interchangeably and refer to the “total”testosterone concentration which is the sum of the bioavailabletestosterone including free and bound testosterone concentrations.Unless otherwise specified, these values are “observed” testosteroneconcentrations without adjusting or correcting for the base-line serumtestosterone levels in the subject(s). As with any bio-analyticalmeasure, for increased consistency, the method employed to measureinitial serum testosterone levels should be consistent with the methodused to monitor and re-measure serum testosterone levels during clinicaltesting and testosterone therapy for a subject. Unless otherwise stated,“testosterone concentration” refers to serum total testosteroneconcentration.

Average serum testosterone concentrations can be determined usingmethods and practices known in the art. For example, the averagebaseline plasma testosterone concentration of a human male is thearithmetic mean of the total plasma testosterone concentrationdetermined on at least two consecutive time points that are reasonablyspaced from each other, for example from about 1 hour to about 168 hoursapart. In a particular case, the plasma testosterone concentration canbe determined on at least two consecutive times that are about 12 hoursto about 48 hours apart. In another particular method, the plasmatestosterone concentration of the human male can be determined at a timebetween about 5 o'clock and about 11 o'clock in the morning. Further,the plasma testosterone concentration can be the determined by standardanalytical procedures and methods available in the art, such as forexample, automated or manual immunoassay methods, liquid chromatographyor liquid chromatography-tandem mass spectrometry (LC-MSMS) etc.

As used herein, the term “AUC_(t1-t2)” is the area under the curve of aplasma-versus-time graph determined for the analyte from the time “t1 totime t2”. Wherein t1 and t2 are times (in hours) post dosing. ForExample, t1 could be 1 hour and t2 could be 2 hours.

As used herein, the term “C_(avg),” “C_(ave),” or “C-average” are usedinterchangeably, and is determined as the AUC_(t1-t2) mean AUC dividedby the time period (|t1-t2|). For example, C_(avg t0-t8) is the averageplasma concentration over a period of 8 hours from t1=0 to t2=8 hours)post-dosing determined by dividing the AUC t_(0-t8) value by 8.Similarly, C_(avg t0-t12) is the average plasma concentration over aperiod of 12 hours post-dosing determined by dividing the AUCt_(0-t12)value by 12 (t1=0-t2=12). Similarly, C_(avg t12-t24) is the averageplasma concentration over a period of 12 hours post-dosing determined bydividing the AUCt_(12-t24) value by 12 (t1=12-t2=24); C_(avg-t24) is theaverage plasma concentration over a period of 24 hours post-dosingdetermined by dividing the AUCt_(0-t24) value by 24 (t1=0-t2=24), and soon. Unless otherwise stated, all C_(avg) values are considered to beC_(avg-t24) and unless otherwise stated, all the time values areexpressed in hours (h). For example, the term C_(avg t0-t24) denotesC_(avg) from time zero (0) to 24 hours post dosing.

As used herein, “C_(t)” refers to the serum concentration oftestosterone at time “t” prior to or after administration of the dosageof the current invention. The time “t” is generally in hours, unlessotherwise specified. For example, a C_(t) of “C_((−2 to 0)) refers toserum testosterone concentration measured in sample collected betweenthe time of about 2 hours before and just immediately prior to dosageadministration to the subject tested. Similarly, C_(t) of “C_((2 to 4))”refers to serum testosterone concentration measured in sample collectedbetween the time of about 2 hours and 4 hours after administration of adosage to the subject tested.

As used herein, the term (17-β)-Hydroxy-4-Androsten-3-one refers to achemical having an IUPAC name of(8R,9S,10R,13S,14S,17S)-17-Hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-oneand a CAS number of 58-22-0. (17-β)-Hydroxy-4-Androsten-3-one estersgenerically refers to compounds having the(17-β)-Hydroxy-4-Androsten-3-one structure but the hydroxyl group isesterified with e.g., an alkanoic acid. For example,(8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-ylundecanoate is the IUPAC name for (17-β)-Hydroxy-4-Androsten-3-oneesterified with a straight chain saturated 11 carbon long alkanoic acidcalled undecanoic acid. Undecanoic acid is the IUPAC name for thealkanoic acid having CAS number 112-37-8. In a snore specific aspect,(17-β)-Hydroxy-4-Androsten-3-one esters refers to those(17-β)-Hydroxy-4-Androsten-3-one esters specifically disclosed herein.In one specific aspect, refers to the tridecanoate(17-β)-Hydroxy-4-Androsten-3-one ester (referred to herein as(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate or the tridecanoic ester of(17-β)-Hydroxy-4-Androsten-3-one and the such (CAS No. 488836-58-4)).Tridecanoic acid has an IUPAC name of Tridecanoic acid (CAS number638-53-9) and is a 13 carbon straight chain saturated alkanoic acid.(17-β)-Hydroxy-4-Androsten-3-one has the following structure:

Solid state EAPI, e.g., solid state (17-β)-Hydroxy-4-Androsten-3-oneesters described herein, can exist in different crystalline forms aswell as in non-crystalline forms. A non-crystalline solid EAPI isreferred to herein as an “amorphous form,” which is a disorderedarrangement of EAPI molecules. Different crystalline forms of the EAPI,e.g., of a specific (17-β)-Hydroxy-4-Androsten-3-one ester, arise fromdifferent packing of the EAPI molecules in the solid state, resulting indifferent crystal symmetries and/or unit cell parameters. Crystallineforms are identified or characterized by any suitable methods e.g.,x-ray diffraction (see, e.g., Remington's Pharmaceutical Sciences, 18thed., Mack Publishing, Easton Pa., p 173 (1990); The United StatesPharmacopeia, 23rd ed., pp. 1843-1844 (1995)). Such differentcrystalline forms are referred to herein as “polymorphic forms” or“non-solvated forms,” which means that they are essentially free ofresidual solvents e.g., organic solvents. If the substances incorporatestoichiometric or non-stoichiometric amounts of water (“hydrate” as usedherein), or any other solvent (“solvate” as used herein), in the crystalstructure, these are referred to herein as a “pseudopolymorphic form.”

The term “amorphous form” as used herein in connection with solid stateEAPI refers to an EAPI that is a non-crystalline solid (i.e., not in acrystalline form), which is a disordered arrangements of EAPI molecules.Typically, solid state amorphous EAPI has no long-range periodic atomicstructure as determined by X-ray powder diffraction (XRPD). The XRPDpattern of amorphous EAPI appears as a halo with no distinctive peaks.Amorphous material for some compounds can be obtained by a number ofmethods known in the art, including, but not limited to, heating, meltcooling, rapid melt cooling, solvent evaporation, rapid solventevaporation, desolvation, sublimation, grinding, cryo-grinding orfreeze-drying.

The term “crystal” as used herein refers to a solid structure, typicallyformed by a solidification of an EAPI, that generally has a regularatomic structure (characteristic shapes and cleavage planes formed bythe arrangement of molecules in a pattern referred to as a “lattice”).

The term “seeding” as used herein refers to starting or promoting acrystallization event using a small amount of material.

As used herein, the term “Triton X100” or Triton “X-100” is a non-ionicdetergent and refers to a composition as known as polyethylene glycolp-(1,1,3,3-tetramethylbutyl)-phenyl ether, octyl phenol ethoxylate,polyoxyethylene octyl phenyl ether, 4-octylphenol polyethoxylate, Mono30, TX-100, t-octylphenoxypolyethoxyethanol, or Octoxynol-9 andassociated with CAS NO. 9002-93-1.

A “pharmaceutical composition” as used herein refers to a compositioncomprising or prepared from a solid state form of a(17-β)-Hydroxy-4-Androsten-3-one ester and a pharmaceutically acceptablecarrier or excipient. A “unit dosage form” as used herein refers to amedicament prepared from or comprising a pharmaceutical composition andincludes tablets, capsules, caplets, gelcaps, ampoules, suspensions,solutions, gels, dispersions and other dosage units typically associatedwith parenteral, enteral, topical or other forms of administration of anEAPI to a subject in need thereof.

A “pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” or similar term refers to one or multiple components oringredients that is acceptable (1) as being compatible with the otheringredients in compositions or formulations comprising an EAPI and (2)are not deleterious or overly deleterious to a subject to whom thecomposition or formulation is to be administered. Excipients includewithout limitation, benzyl benzoate, cottonseed oil,N,N-dimethylacetamide, an alcohol such as methanol, ethanol, glycerol,peanut oil, a polyethylene glycol (“PEG”) (low molecular weight (200-),vitamin E, castor oil, poppy seed oil, peppermint oil, borage oil,propylene glycol, medium molecular and high molecular weight), saffloweroil, sesame oil, soybean oil or other vegetable oil. Excipients caninclude dissolution aids typically used for EAPIs that are sparinglysoluble or insoluble in water such as a cyclodextrin or a cyclodextrinderivative such as β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin andCAPTISOL™ (sulfobutyl ether-β-cyclodextrin) and a PEG or PEG derivativesuch as CREMOPHOR™ (a polyethoxylated castor oil). Any solid excipientmay be a fine powder or granulated. Excipient, as used herein mayoptionally exclude one or more excipients, e.g., chloroform, dioxane,vegetable oil, DMSO, other another excipient (e.g., those listed hereinor elsewhere) or any combination of these. Excipients include one ormore components typically used in the pharmaceutical formulation arts,e.g., in some instances one, two, or more of fillers, binders,disintegrants, dispersants, preservatives, glidants, surfactants,stabilizers (e.g., antioxidants like ester of ascorbic acid (e.g.,ascorbyl palmitate)) and lubricants. Exemplary excipients includepovidone, crospovidone, corn starch, carboxymethyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, gum arabic,polysorbate 80, butylparaben, propylparaben, methylparaben, BHA, EDTA,sodium lauryl sulfate, sodium chloride, potassium chloride, titaniumdioxide, magnesium stearate, castor oil, olive oil, vegetable oil, fattyacid (e.g., C8 to C22 straight or branched chain, saturated orunsaturated fatty acids like oleic acid, stearic acid, or myristicacid), mono-, di-, or tri-glycerides or mixtures thereof (e.g., of C8 toC22 straight or branched chain, saturated or unsaturated fatty acidslike oleic acid, stearic acid, myristic acid, linoleic acid, palmiticacid, or a combination thereof) buffering agents such as sodiumhydroxide, monobasic sodium phosphate, dibasic sodium phosphate,potassium hydroxide, monobasic potassium phosphate, dibasic potassiumphosphate, tribasic potassium phosphate, potassium carbonate, potassiumbicarbonate, ammonium hydroxide, ammonium chloride, saccharides such asmannitol, glucose, fructose, sucrose or lactose any of which may becompressible or any of which may be spray dried.

Carriers (e.g., pharmaceutically acceptable excipients or additives) andmethods of preparing oral pharmaceutical compositions comprising(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (or any other of the(17-β)-3-Oxoandrost-4-en-3-one esters) are available to the skilledartisan in view of this application which typical involve a specificsolid state form of the EAPI.

Carriers and methods of manufacture of non-oral pharmaceuticalcompositions comprising (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (orany other of the (17-β)-3-Oxoandrost-4-en-3-one esters) are available tothe skilled artisan in view of this application which typically involvea specific solid state form of the EAPI. In one embodiment, apharmaceutical composition and unit dosage form for injectableadministration (e.g., parenteral administration, intramuscular injection(e.g., depot), subcutaneously) is provided. In one example, thepharmaceutical composition comprises or is prepared from(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a vehicle comprising apharmaceutically acceptable oil. In one aspect, the vehicle furthercomprises a co-solvent. In one aspect, the pharmaceutically acceptableoil is castor oil. In one aspect, the co-solvent is benzyl benzoate.Other types of co-solvents may be applicable for use in combination withthe vehicle (e.g., castor oil), such as ethanol or benzyl alcohol orothers. In one aspect, the co-solvents are those which are capable ofdissolving the solid state (17-β)-3-Oxoandrost-4-en-17-yl tridecanoateand is miscible with castor oil. In some aspects, the co-solvent(s) issuitable for dissolving about 100-500 mg, such as 250 mg of solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in 1 mL of the co-solventwithin 50 minutes at 40° C. or within 20 minutes at 60° C. In someaspects, the compositions have the co-solvent present in the vehicle atconcentrations ranging from 10 to 90 volume % (“v %”). In some aspects,the concentration of the co-solvent in the vehicle ranges between 15 to90 v %, between 20 to 85 v %, between 45 to 85 v % or 55 to 85. Thus, insome aspects, the vehicle comprises castor oil in a volume concentrationranging between 20 to 85 v %. The concentration of castor oil in thevehicle ranges between 25 to 60 v %, such as between 25 to 55 v %. In apreferred embodiment, the concentration of castor oil in the vehicleranges between 25 to 50 v %, such as between 25 to 45 v % or 25 to 40 v%. Other formulations are also contemplated including those having (orprepared from) different amounts of a particular form or forms of solidstate EAPI, different vehicles, different co-solvents, or a combinationthereof. In some aspects, the parenteral formulation is injected as adepot (e.g., intramuscular). In some aspects, the formulation isinjected subcutaneously. The amount injected depends on a number offactors, but preferably is in the range of 0.100 mL to 5 mL and providessufficient levels of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate ortestosterone to the individual to maintain a hypogonadal male in aeugonadal range for 1 day or more, or more than 2, 3, 4, 5, 6, 7, 8, 9,10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, or 180 ormore days per injection.

Reference will now be made in detail to specific embodiments of theinvention. While the invention will be described in conjunction withsuch embodiments, it will be understood that it is not intended to limitthe invention to those embodiments. To the contrary, it is intended tocover alternatives, variants, modifications, and equivalents as may beincluded within the spirit and scope of the invention as defined by theappended claims.

(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate can be prepared by a numberof synthetic routes (as well as other corresponding esters in ananalogous fashion). In one aspect, (17-β)-3-Oxoandrost-4-en-17-yltridecanoate is prepared for the corresponding alcohol via anesterification reaction with an activated fatty acid and(17-β)-Hydroxy-4-Androsten-3-one (of n-tridecanoic acid, IUPAC nametridecanoic acid, CAS number 638-53-9) e.g., an acid chloride oranhydride, in a suitable solvent under suitable conditions to producethe product. In one aspect, the (17-β)-Hydroxy-4-Androsten-3-one isprepared from a phytosterol or cholesterol or any other suitablestarting material. The product is worked up via any number oftechniques. For example, the product is dissolved in a solvent (e.g.,organic solvent such as heptanes or any other solvent); washedsuccessively with e.g., cold water (2×), 0.05 N NaOH, saturated NaHCO₃(2×), water, brine, then dried (e.g., over anhydrous Na₂S0₄ (−50 g),followed by concentration to dryness. Without wishing to be bound bytheory, the inventors have unexpectedly found that crystallization orrecrystallization of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoateprovides solid state EAPI with one or more advantageous properties asdescribed herein.

Thus, according to one embodiment, recrystallized or crystallized solidstate EAPI (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is provided.According to this embodiment (17-β)-3-Oxoandrost-4-en-17-yl tridecanoateis dissolved in a solvent and allowed to crystallize or recrystallize orafter a first crystallization is transferred to another solvent andallowed to crystallize or recrystallize. The crystalline mass can beisolated (e.g., filtered by suction), optionally washed (e.g., withwater), optionally dried (e.g., over phosphorous pentoxide) andoptionally re-crystallized from another solvent e.g., oleic acid,hexane, heptanes, etc. In one aspect, the solvent (for crystallizationor recrystallization) is an alcohol (e.g., ethanol, methanol, orpropanol), fatty acid (e.g., oleic acid, linoleic acid, or linoleicacid), alkane (e.g., hexane, heptane, pentane, or halogenated alkane),oil (e.g., vegetable oil, castor oil, or hydrogenated oil), or any othersuitable solvent (e.g., pyridine, benzene, or toluene). In this context,a solvent refers to a liquid in which (17-β)-3-Oxoandrost-4-en-17-yltridecanoate is soluble and/or can crystallize from.

Crystalline forms of a substance can be obtained by a number oftechniques, as is known in the art. Exemplary techniques for obtaining,producing, or manufacturing crystalline forms of(17-β)-Hydroxy-4-Androsten-3-one esters include e.g., meltrecrystallization, melt cooling, solvent recrystallization,recrystallization in confined spaces such as, e.g., in nanopores orcapillaries, recrystallization on surfaces or templates such as, e.g.,on polymers, recrystallization in the presence of additives, such as,e.g., co-crystal counter-molecules, desolvation, dehydration, rapidevaporation, rapid cooling, slow cooling, vapor diffusion, sublimation,grinding and solvent-drop grinding.

Typically, crystalline forms of specific(17-β)-Hydroxy-4-Androsten-3-one esters can be distinguished from eachother by one or more physical or analytical properties such as rate ofdissolution, infrared or Raman spectroscopy, x-ray diffractiontechniques such as single crystal and powder diffraction techniques,solid state-NMR (SS-NMR), thermal techniques such as melting point,differential thermal analysis (DTA), differential scanning calorimetry(DSC), thermal gravimetric analysis (TGA) and other methods as disclosedelsewhere in the specification or available to the skilled artisan.Other methods to characterize or distinguish a pseudopolymorph fromanother isostructural polymorph, pseudopolymorph, desolvate or anhydrateinclude elemental analysis, Karl-Fisher titration, dynamic vaporsorption analysis, thermogravimetric-infrared spectroscopic analysis(TG-IR), residual solvent gas chromatography, 1H-NMR etc.

Thus, in one embodiment, a solid state EAPI which is(17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate is provided wherein thesolid state EAPI has one or more advantageous properties compared toother forms such as chemical, crystalline, or polymorphic purity,increased crystallinity, flowability, solubility, dissolution rate,bioavailability, morphology or crystal habit, specific surface andpycnometric density, bulk/tap density, stability (e.g., such as chemicalstability as well as thermal and mechanical stability with respect topolymorphic conversion), stability towards hydration and/or storagestability, a lower degree of hygroscopicity, low content of residualsolvent(s) and advantageous processing and handling characteristics suchas compressibility and bulk density. The solid state EAPI iscrystalline, non-crystalline, or a mixture thereof. For example, thesolid state EAPI is crystalline (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. In another example, thesolid state EAPI is non-crystalline (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. In a specific aspect, thesolid state EAPI is amorphous (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. The solid state EAPI isuseful for administration to a human e.g., the solid state EAPI is(17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate useful for administrationto humans. In specific aspects of this embodiment, the solid state EAPIhas unexpectedly improved dissolution, solubility, bioavailability,bioactivity, fluctuation index, processing, manufacturing, storage,taste, color, aggregates or granules.

In one embodiment, solid state EAPI is provided comprising solid(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In one aspect of thisembodiment, the solid state EAPI is crystalline or non-crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or a mixture thereof. In aspecific aspect, the solid state EAPI is amorphous(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. The solid state EAPI isparticularly suitable for administration to a human. In one aspect, thesolid state EAPI is a specific crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate form (e.g., substantiallysimilar to that characterized in the Examples and figures by XRD andDSC). In a specific aspect, the solid state EAPI is crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate having 50%, 40%, 30%, 20%,10%, 5%, 2%, or 1% or less by total weight of EAPI of amorphous(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another aspect, thesolid state EAPI is a solvate or a pseudopolymorph of(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another aspect, thesolid state EAPI is a polymorph of (17-β)-3-Oxoandrost-4-en-17-yltridecanoate. In another aspect, the solid state EAPI is a hydrate of(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In yet another aspect, thesolid state EAPI is crystalline (17-β)-3-Oxoandrost-4-en-17-yltridecanoate form having 50%, 40%, 30%, 20%, 10%, 5%, 2%, or 1% or lessby total weight of EAPI of other crystalline forms of(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In one aspect, the solidstate EAPI is crystalline (17-β)-3-Oxoandrost-4-en-17-yl tridecanoatehaving a melting point in the range of 30 to 150° C., 40 to 120° C., 50to 100° C., 55 to 90° C., 60 to 85° C., 60 to 80° C., or 66 to 77° C. asdetermined by differential scanning calorimetry. In one aspect, thesolid state EAPI is crystalline (17-β)-3-Oxoandrost-4-en-17-yltridecanoate having a melting point in the range of 60 to 85° C., 62 to83° C., 64 to 81° C., 64 to 79° C., 66 to 77° C., 68 to 75° C., or 69 to73° C. as determined by differential scanning calorimetry. In oneaspect, the solid state EAPI has a melting point as determined bydifferential scanning calorimetry characteristic of a single crystalform or non-amorphous (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. Inone aspect, the solid state EAPI is crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate having 1, 2, 3, 4, 5, 6 ormore peaks as determined by XRD corresponding to those in FIG. 6 (at agiven count threshold of above 250, 500, 750, 1000, or 1250). In againyet another aspect, the solid state EAPI is amorphous(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate having 50%, 40%, 30%, 20%,10%, 5%, 2%, or 1% or less by total weight of crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In one aspect, the solidstate EAPI is crystalline (17-β)-3-Oxoandrost-4-en-17-yl tridecanoatewhich is not milled or is milled, micronized, or nanosized. In oneaspect, the solid state EAPI is (17-β)-3-Oxoandrost-4-en-17-yltridecanoate having a d₅₀ of greater than 1000 μm, from 355 to 1000 μm,from 180 to 355 μm, from 125 to 180 μm, from 90 to 125 μm, from 1 to 90μm, or less than 1 μm. In one aspect, the solid state EAPI is(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate having a particle size ofless than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50μm, from 50 μm to 250 μm, from 250 μm to 500 μm, from 500 μm to 1000 μm,or greater than 1000 μm. In one aspect, the solid state EAPI is(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate having a D₁₀, D₅₀, or D₉₀that is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from1 to 50 μm, from 50 to 250 μm, from 250 to 500 μm, from 500 to 1000 μm,or greater than 1000 μm. In one aspect, the solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is a composition havinggreater than 1 g, 2 g, 50 g, 500 g, 1 kg, 10 kg, 50 kg, 100 kg, 200 kg,500 kg, 1000 kg, 2000 kg, 5000 kg, or 10,000 kg solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In one aspect, the releaseprofile of the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate does notchange substantially as a function of time.

Production of Amorphous EAPI or Different Crystal Forms of Solid StateEAPI

Described herein are different forms of EAPI, particularly(17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. The identification ofdifferent forms of EAPI yields new, improved properties related to theuse of the EAPI.

A number of different forms, including crystalline forms of(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate may exist. Crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate may be produced according tothe figures and as described herein or by other methods available to theordinary skilled artisan in view of this disclosure to obtain solidstate forms having desirable properties.

Amorphous (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is another solidstate EAPI form. A number of techniques are available for preparingamorphous (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. For example,flash evaporation, lyophilization, quench cooling of the melt, spraydrying, grinding, supercritical fluids are non-limiting techniques thatcan be used to make amorphous EAPI. In some aspects, the amorphous(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is metastable.

Experimental Instrumentation and Conditions for Analyzing Solid StateEAPI

A variety of techniques may be used to identify or characterize solidstate EAPI, particularly solid state (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate.

Fourier Transform-Raman Spectroscopy (“FT-Raman”) is useful forcharacterizing and identify solid state forms of(17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate. For example, differentsolid EAPI forms may be characterized using a Bruker RFS 100 instrument,with Nd:YAG 1064 nm excitation, 300 mW laser power, Ge detector, using64 scans over the range of 25-3500 cm⁻¹, and with 2 cm⁻¹ resolution. Asis understood by the ordinary skilled artisan, the parameters andinstrumentation for FT-Raman may be modified depending on theinstrument, the solid state EAPI and goal(s) of the analysis.

Another useful technique for characterization is Power X-ray Diffraction(“XRD”). XRD can be performed with a Bruker D8 Advance X-raydiffractometer with CuKα-radiation. The standard measuring conditionsare e.g., tube power 35 kV/45 mA; step size 0.017° (2θ); step time 105±5sec; scanning range 2°-50° (2θ); divergence slit equal to variable V12;sample rotation; a Vantec1 detector; the opening angle 3°; channelnumber 360±10; the y-axis shows the value intensity/number of activedetector channels/sec; silicon single crystal sample holders; and thesample dimensions depth/diameter was 0.1 mm/⁻12 mm. As is understood bythe ordinary skilled artisan, the parameters and instrumentation forpowder XRD may be modified depending on the instrument, the solid stateEAPI and goal(s) of the analysis. In one embodiment, the solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate EAPI is crystalline orsubstantially crystalline as indicated by XRD. An example of an XRDspectra is shown in FIG. 6 for crystalline or substantially crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. FIG. 6 shows well definedpeaks corresponding to crystalline or substantially crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate with little or no amorphousEAPI (as indicated by the absence of an “amorphous halo” in the spectrain the 20-40 degree 2θrange). In one aspect, the solid state EAPIdescribed herein has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more ofthe peaks that corresponds to those in FIG. 6 that have above 100, 200,300, 400, 500, 600, 700, 800, 900, 1000 or 1200 counts.

Thermogravimetric-Fourier transform Infrared Spectroscopy (“TG-FTIR”)can also be used to characterize or analyze solid state EAPI. Forexample, TG-FTIR can be performed with a Netzsch Thermo-Microbalance TG209 coupled with a Bruker FT-IR Spectrometer Vector 22, using analuminum crucible (open or with a microhole), under a nitrogenatmosphere, and e.g., at a heating rate of 10° C./min over the range of25° C. to 350° C. As is understood by the ordinary skilled artisan, theparameters and instrumentation for TG-FITR may be modified depending onthe instrument, the solid state EAPI and goal(s) of the analysis.

Characterization/Analysis of EAPI can also be performed usingDifferential Scanning calorimetry (“DSC”). For example, DSC can beperformed with a Perkin Elmer Differential Scanning calorimeter, usingclosed gold crucibles, a heating rate of 10° C. min⁻¹ or 20° C. min⁻¹over a range from 0° C. to 250° C. (or e.g., over a range from 5° C. to150° C.). See e.g., Example 3. As is understood by the ordinary skilledartisan, the parameters and instrumentation for DSC may be modifieddepending on the instrument, the solid state EAPI and goal(s) of theanalysis.

Thus, in yet another embodiment, a solid state EAPI, e.g.,(17-β)-3-Oxoandrost-4-en-17-yl undecanoate,(17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate, is provided which has amelting point in the range of about 20 to 150° C., as determined by DSC.In a more specific embodiment, a solid state EAPI is provided which hasa melting point in the range of about 55 to 80° C., as determined byDSC. In another specific embodiment, a solid state EAPI is providedwhich has a melting point in the range of about 65 to 75° C., asdetermined by DSC. In one aspect of this embodiment, the melting pointof the solid state EAPI is characteristic of a single physical form ofEAPI e.g., a single crystalline form or amorphous EAPI.

In yet another embodiment, a pharmaceutical composition or unit dosageform having a solid state EAPI (e.g., (17-β)-3-Oxoandrost-4-en-17-ylundecanoate, (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate,(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, or(17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate) is provided where thepharmaceutical composition has a melting point in the range of about 10to 200° C., as determined by DSC. The pharmaceutical composition of thisembodiment, comprises or is prepared from solid state EAPI and one ormore pharmaceutically acceptable carriers. In a more specificembodiment, a pharmaceutical composition is provided having or preparedfrom solid state EAPI where the solid state starting material has amelting point in the range of about 30 to 150° C., as determined by DSC.In a more specific embodiment, a pharmaceutical composition is providedhaving or prepared from solid state EAPI where the solid state startingmaterial has a melting point in the range of about 60 to 85° C., 62 to83° C., 64 to 81° C., 64 to 79° C., 66 to 77° C., 68 to 75° C., or 69 to73° C., as determined by DSC. In a specific embodiment, a pharmaceuticalcomposition is provided having or prepared from solid state which has amelting point of EAPI in the range of about 40 to 90° C., as determinedby DSC. In one aspect of this embodiment, the melting point of thepharmaceutical composition or unit dosage form does not have a peakcorresponding to the melting point peak of the EAPI from which it wasprepared as determined by DSC. For example, the melting point of thestarting solid state EAPI is in the range of 69-73° C. and when themelting point of the pharmaceutical composition comprising the EAPI isdetermined the melting point peak in the range of 69-73° C. disappearsis diminished or substantially diminished.

Dynamic Vapor Sorption (DVS) analysis is another technique forcharacterizing and analyzing EAPI. For example, DVS can be performedwith a Surface Measurement Systems DVS-1 water vapor sorption analyzer.The experiments can be run by placing the sample on a quartz holder ontop of a microbalance, and allowing the sample to equilibrate at 50%relative humidity (r.h.) before starting the pre-defined humidityprogram. The program can proceed e.g., in the following steps: 1 hour at50% r.h.; 50% to 0% r.h. at a rate of 5% r.h. change per hour; 5 hoursat 0% r.h; 0% r.h to 96% r.h. at 5% r.h change per hour; 5 hours at 95%r.h.; 95% r.h. to 50% r.h. at a rate of 5% r.h. change per hour, andfollowed by one hour at 50% r.h. As is understood by the ordinaryskilled artisan, the parameters and instrumentation for DVS may bemodified depending on the instrument, the solid state EAPI and goal(s)of the analysis.

High performance liquid chromatography (HPLC) is also useful foranalyzing or characterizing EAPI. In some of the embodiments, the purityof the amorphous form of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate asmeasured by high pressure liquid chromatography is greater than about90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%,about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%,about 98.5%, about 99.0%, about 99.5%, or about 99.9% total area underthe curve as observed at a suitable wavelength e.g., about 240 nm orabout 242 nm. In some embodiments, the amorphous form of(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is about 100.0% pure asmeasured by HPLC as area under the curve as observed at a suitablewavelength, e.g., at a wavelength of from about 200 nm to about 300 nm,e.g., about 240 nm or 242 nm.

In some of the embodiments, the purity of a crystalline form of(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate as measured by HPLC isgreater than about 90%, about 90.5%, about 91.0%, about 91.5%, about92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%,about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about99.9% total area under the curve as observed at a suitable wavelengthe.g., about 240 nm or about 242 nm. In some embodiments of theinvention, a crystalline form of (17-β)-3-Oxoandrost-4-en-17-yltridecanoate is about 100.0% pure as measured by HPLC as area under thecurve as observed at a suitable wavelength, e.g., at a wavelength offrom about 200 nm to about 300 nm, e.g., about 240 nm or 242 nm.

As is understood by the ordinary skilled artisan, solid state NMR andother techniques can be used to analyze or characterize solid EAPI andforms thereof in view of this disclosure.

Production of Different Sizes of Solid State EAPI

Composition having different particles sizes or distributions ofparticles sizes can be produced by any suitable method. Micronizationtechniques can be based on friction to reduce particle size; suchmethods include milling, bashing and grinding. Another technique ofproducing different sized EAPI particles involves supercritical fluidswhere the EAPI is dissolved in a solvent at high temperature andpressure and they sprayed out of a nozzle, causing the formation of EAPIparticles of particular sizes or within particular sizeranges/distributions. Some basic supercritical fluid techniques are RESSprocess (Rapid Expansion of Supercritical Solutions), the SAS method(Supercritical Anti-Solvent) and the PGSS method (Particles from GasSaturated Solutions).

Particle Size and Morphology Analysis

Solid state EAPI particles can be analyzed by a number of techniques.For example, Particle size can be analyzed by photon correlationspectroscopy (PCS) using a Malvern ZetaSizer 2000 HS (MalvernInstruments, Malvern, UK). The measuring mode applied can be e.g.,Contin-Auto mode. PCS yields the mean diameter of the bulk population(z-average) and a polydispersity index (PI) ranging from 0(monodisperse) through 0.10-0.20 (relatively monodisperse) to >0.5 for abroad size distribution. The measuring range of PCS is approximately 3nm-3 μm. As is understood by the ordinary skilled artisan, theparameters and instrumentation for PCS may be modified depending on theinstrument, the solid state EAPI and goal(s) of the analysis.

Solid state EAPI can also be analyzed by electron microscopy. Solidparticles are deposited on metallic stubs then placed in liquid nitrogenand dried under vacuum. The freeze-dried particles are coated uniformlywith gold. All samples are examined for morphology and surfaceproperties using a scanning electron microscope (e.g., Joel, SEM, JSM-25SII, Tokyo, Japan). Particle size, polydispersity index and zetapotential were initially measured by a laser particle size analyser(Submicron Particle Size Analyser 90 plus, Brookhaven Instrument Co.,Holtsville, N.Y., USA). An aliquot of solid state EAPI particles can bediluted with e.g., 3 ml of deionized water. The diluted EAPI samples areloaded into a 4 ml cuvette and the particle size and zeta potentialmeasurement can be conducted at e.g., ambient temperature. As isunderstood by the ordinary skilled artisan, the parameters andinstrumentation for electron microscopy may be modified depending on theinstrument, the solid state EAPI and goal(s) of the analysis.

The particle size can also be estimated by PXRD e.g., by applying theSherrer equation which relates the size particles (e.g., crystalparticles or crystallites), in a solid to the broadening of a peak in adiffraction pattern.

Release Profile of Solid State EAPI

In one embodiment, the release profile (e.g., a profile comprising 2, 3,4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apartor a single time point) of solid state (17-β)-3-oxoandrost-4-en-17-yltridecanoate EAPI does not change substantially as a function of storagetime. In one aspect, the release profile of solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate does not substantiallychange over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, or 16 weeks. In one aspect, the release profile of solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate does not substantiallychange over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, or 16 months. In one aspect, the release profiles is tested using aUSP type 2 apparatus at 100 rpm in about 1000 mL 8% Triton X-100solution in water at a specific temperature e.g., 20.0, 37.0 or 40.0° C.(±0.5). In one aspect, a release profile that does not substantiallychange over a period of time refers to a release profile that changes byless than plus/minus 50%, 40%, 30%, 20%, or 10% or less of amount(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate released at one or morespecific time point under specific conditions.

Pharmaceutical Compositions Having Solid State EAPI

The pharmaceutical compositions and dosage forms (e.g. capsule ortablet) described herein prepared from or comprising solid(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate EAPI can include a varietyof pharmaceutically acceptable carriers known in the art. Non-limitingexamples of components that can be included as components of thepharmaceutical carrier include lipophilic surfactants, hydrophilicsurfactants, triglycerides, fatty acid (C8 to C22), fatty acidglycerides (mono-, di-, tri-, or a combination thereof), or acombination thereof.

In one embodiment, the pharmaceutical composition or dosage formcomprises, or is prepared from, solid (17-β)-3-Oxoandrost-4-en-17-yltridecanoate EAPI as described herein. In a specific aspect of thisembodiment, the solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate EAPIof the pharmaceutical composition or dosage form is amorphous orsubstantially amorphous or amorphous-like. Amorphous-like refers to aphysical state of the EAPI in a dosage form or pharmaceuticalcomposition in which a substantial amount of the EAPI is not in astructured crystal state (e.g., dissolved in a solvent). In anotherspecific aspect of this embodiment, the solid(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate EAPI of the pharmaceuticalcomposition or dosage form is amorphous or substantially free ofcrystalline EAPI. In yet another aspect, the pharmaceutical compositionor dosage form is prepared from crystalline solid(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In yet another aspect, thepharmaceutical composition or dosage form is prepared from a specificcrystal form solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In yetanother aspect, the pharmaceutical composition or dosage form isprepared from the crystal form of solid (17-β)-3-Oxoandrost-4-en-17-yltridecanoate as characterized in the Examples by XRD and DSC.

In yet another aspect, the pharmaceutical composition or dosage form isprepared from crystalline solid (17-β)-3-Oxoandrost-4-en-17-yltridecanoate and the pharmaceutical composition comprises amorphous oramorphous-like solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In yetanother aspect, the pharmaceutical composition or dosage form isprepared from crystalline solid (17-β)-3-Oxoandrost-4-en-17-yltridecanoate substantially free of amorphous(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In yet another aspect, thepharmaceutical composition or dosage form is prepared from crystallinesolid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free ofamorphous solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and thepharmaceutical composition comprises amorphous or amorphous-like solid(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free ofcrystalline solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In yetanother aspect, the pharmaceutical composition or dosage form isprepared from amorphous solid (17-β)-3-Oxoandrost-4-en-17-yltridecanoate substantially free of crystalline solid(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and the pharmaceuticalcomposition comprises amorphous or amorphous-like solid(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free ofcrystalline solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate.

In one embodiment, the pharmaceutical composition or unit dosage formhas improved release properties as compared to solid state EAPI (e.g.,from which the composition or dosage form is made) without any carriersor excipients. According to this embodiment, a pharmaceuticalcomposition or unit dosage form having a particular amount of(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., 3 mg or more, 4 mg ormore, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mgor more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more,125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mgor more, 250 mg or more, 275 mg or more, or 300 mg or more) releasesmore (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate than a composition (nota pharmaceutical composition or unit dosage form e.g., bulk EAPI) ofcrystalline EAPI having an equivalent amount of(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate at a specified time point(e.g., 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10min, 11 min, 12 min, 15 min, 20 min, 25 min, 30 min, 35 min, 45 min, 60min, 75 min, 90 min, 105 min or 120 min) in a USP Type 2 apparatus inabout 1000 mL 8% Triton X100 solution in water at a specific temperature(e.g., 20.0, 37.0 or 40.0° C. (±0.5)) at 100 rpm. Releases more in thiscontext refers to releasing more than 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90% or 100% or more than the bulk EAPI.

In one embodiment, the pharmaceutical composition or unit dosage formhaving (or made from) solid state EAPI has a release profile (e.g.,single time point or multiple time points) of(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that does not changesubstantially as a function of storage time as measured using a USP type2 apparatus in about 1000 mL 8% Triton X100 solution in water atspecific temperature (e.g., 20.0, 37.0 or 40.0° C. (±0.5)) at 100 rpm.In one aspect, the release profile does not substantially change over aperiod of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16weeks. In one aspect, the release profile does not substantially changeover a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or16 months. In one aspect, a release profile that does not substantiallychange over a period of time refers to a release profile that changes byless than plus/minus 50%, 40%, 30%, 20%, or 10% or less of amount(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate released at one or morespecific time point under specific conditions.

In one embodiment, the unit dosage form or pharmaceutical composition asdescribed herein comprising, or prepared from, solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceuticallyacceptable carrier, wherein the dosage form or pharmaceuticalcomposition releases 20% or more (17-β)-3-Oxoandrost-4-en-17-yltridecanoate as measured with a USP Type 2 apparatus having 1000 mL 8%Triton X100 solution in water at thirty minutes at a specifictemperature at 100 RPM than a pharmaceutical composition or dosage formcomprising or prepared from an equivalent amount of solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that does not release morethan 1% of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate as measured witha USP Type 2 apparatus having 1000 mL 8% Triton X100 solution in waterat thirty minutes, is provided. In one aspect, the bioavailability(e.g., equivalent total dose single dose administration) of apharmaceutical composition or unit dosage form releasing greater than10, 20, 30, 40, or 50% or more at 1 hour; 40, 50, 60, or 70% or more at2 hours; 50, 60, 70, or 80% or more at 3 hours; 60, 70, 80, or 90% ormore at 4 hours; or a combination thereof, is substantially improvedover a of a pharmaceutical composition or unit dosage form releasingthat release less than 50, 45, 35, 30, 25, 20, or 10% at 1 hour; lessthan 70, 65, 60, 55, 50, 45, 40, 35, 30, 25 or 25% at 2 hours; less than80, 70, 60, 50, 40, or 30% at 3 hours; less than 90, 85, 80, 75, 70, 60,50, or 40 at four hours or a combination thereof. In this context,substantially improved refers to a 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,1.8 or more increase in either AUC_(1-inf) or AUC_(o-t).

In another embodiment, the pharmaceutical composition or unit dosageform having or made from solid state EAPI has a release profile (e.g.,single or multiple point) of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoateusing a USP type 2 apparatus in about 1000 mL 8% Triton X100 solution inwater at a specific temperature (e.g., 20.0, 37.0 or 40.0° C. (±0.5)) at100 rpm that releases at least 10, 20, 30, 40, 50, 60, 70, 75, 80, 85,90, 95, 96, 97, 98, or 99% at 15, 20, 30, 40, 45, 50, 60, 90, 120, 180,240, or 300 minutes. In a specific aspect, the pharmaceuticalcomposition or unit dosage form having or made from solid state EAPI hasa release profile that releases greater than 85% at 4 hours; greaterthan 70% at 2 hours; or greater than 60% at 1 hour. In a specificaspect, the pharmaceutical composition or unit dosage form having ormade from solid state EAPI has a release profile that releases less than100% at 15 minutes or less than 100% at 30 minutes.

In one embodiment, the pharmaceutical composition or unit dosage formhaving EAPI has a release profile of (17-β)-3-Oxoandrost-4-en-17-yltridecanoate using a USP type 2 apparatus in about 1000 mL 8% TritonX100 solution in water at a specific temperature (e.g., 20.0, 37.0 or40.0° C. (±0.5)) at 100 rpm that releases less than 10, 20, 30, 40, 50,60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% at 15, 20, 30, 40, 45,50, 60, 90, 120, 180, 240, or 300 minutes. In a specific aspect, thepharmaceutical composition or unit dosage form having or made from solidstate EAPI has a release profile that releases greater than 85% at 4hours; greater than 70% at 2 hours; or greater than 60% at 1 hour.

In some embodiments, the pharmaceutically acceptable carrier of thecomposition can include a lipophilic additive. In some embodiments, thelipophilic additive can comprise at least about 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 wt % or 100 wt % of thepharmaceutically acceptable carrier. In some embodiments, the lipophilicadditive can comprise at least about 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, or 95 wt % or 100 wt % of the pharmaceuticallycomposition or unit dosage form. Non-limiting examples of lipophilicadditives can include lipophilic surfactants, triglycerides, tocopherol,tocopherol derivatives and combinations thereof. In one embodiment, thelipophilic additive can include a fatty acid or fatty acid glyceride. Inanother embodiment, lipophilic additive can include the fatty acidglyceride, and the fatty acid glyceride can be a monoglyceride, adiglyceride, or mixtures thereof. Non-limiting examples of fatty acidglycerides that can be used in the oral pharmaceutical compositions anddosage forms of the present invention include monoglycerides and/ordiglycerides derived from sources such as maize oil, poppy seed oil,safflower oil, sunflower oil, borage seed oil, peppermint oil, coconutoil, palm kernel oil, castor oil, and mixtures thereof. In oneembodiment, the pharmaceutical composition or dosage form thereofcomprises 50%, 40%, 30%, 20%, 15%, 10%, 5% by weight or less of atriglyceride. In a specific embodiment, the pharmaceutical compositionor dosage form thereof, comprises less than 50% by weight of castor oil.In another embodiment, the composition includes 10 wt % or less oftriglycerides. In a further embodiment, the composition includes 5 wt %or less of triglycerides. In a still a further embodiment, thecomposition includes about 3 wt % or less of triglycerides. In still afurther embodiment, the composition includes about 1 wt % or less oftriglycerides. In another embodiment, the composition is free orsubstantially free of triglycerides. In another embodiment, thecomposition and dosage forms are free of phytosterols and phytosterolfatty acid esters. In one aspect, the lipophilic additive is a C16-C18saturated fatty acid (or has 1, 2, or 3 unsaturations), a mono-, di-, ortriglyceride thereof (including mixtures), or a combination thereof. Ina more specific aspect, the C16-C18 fatty acid is stearic acid, oleicacid. In another specific aspect, the mono-, di-, or triglyceride is aglyceride of palmitic acid, stearic acid, oleic acid, linoleic acid or acombination thereof. For example, glyceryl palmitostearate. In oneaspect, the pharmaceutical composition or unit dosage forms comprises aPEG (e.g., from 200 to 20000 average molecular weight). In one aspect,the pharmaceutical composition or unit dosage forms comprises peppermintoil. In one aspect, the pharmaceutical composition or unit dosage formscomprises menthol.

In another embodiment, the lipophilic additive can include a lipophilicsurfactant. As used herein a surfactant is considered to be a lipophilicsurfactant when it has an HLB value of 10 or less. Various lipophilicsurfactants can be used including, but not limited to mono-,di-glycerides of fatty acids like glyceryl monolinoleate (e.g. Maisine®35-1), mono- and di glycerides of caprylic, capric acid (e.g. Capmul®MCM), glyceryl monooleate, reaction mixtures of alcohols or polyalcoholswith a variety of natural and/or hydrogenated oils such as PEG-5hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9hydrogenated castor oil, PEG-6 corn oil (e.g. Labrafil® M 2125 CS),PEG-6 almond oil (e.g. Labrafil®M 1966 CS), PEG-6 apricot kernel oil(e.g. Labrafil®M 1944 CS), PEG-6 olive oil (e.g. Labrafil®M 1980 CS),PEG-6 peanut oil (e.g. Labrafil®M 1969 CS), PEG-6 hydrogenated palmkernel oil (e.g. Labrafil®. M 2130 BS), PEG-6 palm kernel oil (e.g.Labrafil® M 2130 CS), PEG-6 triolein (e.g. Labrafil® M 2735 CS), PEG-8corn oil (e.g. Labrafil® WL 2609 BS), PEG-20 corn glycerides (e.g.Crovol® M40), PEG-20 almond glycerides (e.g. Crovol® A40), lipophilicpolyoxyethylene-polyoxypropylene block co-polymers (e.g. Pluronic® L92,L101, L121 etc.); propylene glycol fatty acid esters, such as propyleneglycol monolaurate (e.g. Lauroglycol FCC), propylene glycol ricinoleate(e.g. Propymuls), propylene glycol monooleate (e.g. Myverol P-O6),propylene glycol dicaprylate/dicaprate (e.g. Captex® 200), and propyleneglycol dioctanoate (e.g. Captex® 800), propylene glycol mono-caprylate(e.g. Capryol® 90); propylene glycol oleate (e.g. Lutrol OP2000);propylene glycol myristate; propylene glycol mono stearate; propyleneglycol hydroxy stearate; propylene glycol ricinoleate; propylene glycolisostearate; propylene glycol monooleate; propylene glycoldicaprylate/dicaprate; propylene glycol dioctanoate; propylene glycolcaprylate-caprate; propylene glycol dilaurate; propylene glycoldistearate; propylene glycol dicaprylate; propylene glycol dicaprate;mixtures of propylene glycol esters and glycerol esters such as mixturescomposed of the oleic acid esters of propylene glycol and glycerol (e.g.Arlacel® 186); sterol and sterol derivatives such as cholesterol,sitosterol, phytosterol, phytosterol fatty acid esters, PEG-5 soyasterol, PEG-10 soya sterol, PEG-20 soya sterol, and the like; glycerylpalmitostearate, glyceryl stearate, glyceryl distearate, glycerylmonostearate, or a combination thereof; sorbitan fatty acid esters suchas sorbitan monolaurate (e.g. Arlacel 20), sorbitan monopalmitate (e.g.Span-40), sorbitan monooleate (e.g. Span-80), sorbitan monostearate, andsorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitantristearate, sorbitan monoisostearate, sorbitan sesquistearate, and thelike; fatty acids such as capric acid, caprylic acid, oleic acid,linoleic acid, myristic acid, menthol, menthol derivatives, lecithin,phosphatidyl choline, bile salts, and the like, and mixtures thereof. Itis important to note that some lipophilic surfactants may also functionas the solubilizer component of the compositions and oral dosage forms.

In one embodiment, the lipophilic surfactant can be selected from thegroup consisting of glyceryl monolinoleate (e.g. Maisine® 35-1), mono-and di glycerides of caprylic, capric acid (e.g. Capmul® MCM), glycerylmonooleate, propylene glycol mono caprylate, propylene glycol oleate,propylene glycol monostearate, propylene glycol monolaurate, propyleneglycol monooleate, propylene glycol dicaprylate/dicaprate, sorbitanmonooleate, PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castoroil, PEG-9 hydrogenated castor oil, PEG-6 corn oil, PEG-6 almond oil,PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6hydrogenated palm kernel oil, sorbitan monolaurate (e.g. Arlacel 20),sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate,sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitantristearate, sorbitan monoisostearate, and combinations thereof. In someembodiments, the lipophilic surfactants can comprise at least about 10,20, 30, 40, 50, 60, 70, 80, or 90 wt % of the total pharmaceuticallyacceptable carrier. It should be noted that the combinations of two ormore lipophilic surfactants from the same or different classes thereinare also within the scope of this invention and are together can bereferred to as the lipophilic surfactant, unless otherwise stated.

In embodiments of the present invention, the oral pharmaceuticalcompositions or dosage forms (e.g. capsule or tablet) can include ahydrophilic additive. In one embodiment, hydrophilic additive is aselected from the group consisting of hydrophilic surfactant,celluloses—such as hydroxypropyl celluloses low molecular weight, lowviscosity types (e.g. Methocel® ES, E6, E10 E15, LV100 etc. grades) andhydroxypropyl celluloses having higher molecular weight, medium to highviscosity (e.g. Methocel® K4M, K15M, K100M etc.); polyvinylpyrrolidones(e.g. Kollidon k17, K30 etc.); polyvinyl acetates and combinationsthereof.

In one embodiment, the hydrophilic additive can be a hydrophilicsurfactant. A surfactant is considered to be a hydrophilic surfactantwhen it has an HLB value of greater than 10. Non-limiting examples ofhydrophilic surfactants include non-ionic surfactants, ionic surfactantsand zwitterionic surfactants. Specifically the hydrophilic surfactantssuitable for the current invention include, but not limited toalcohol-oil transesterification products; polyoxyethylene hydrogenatedvegetable oils; polyoxyethylene vegetable oils; alkyl sulphate salts,dioctyl sulfosuccinate salts; polyethylene glycol fatty acids esters;polyethylene glycol fatty acids mono- and di-ester mixtures;polysorbates, polyethylene glycol derivatives of tocopherol and the likeIt should be noted that the combinations of two or more hydrophilicsurfactants from the same or different classes are within the scope ofthis invention and are together can be referred to as the hydrophilicsurfactant unless explicitly specified. In one embodiment, thehydrophilic additive can be a hydrophilic surfactant. Non-limitingexamples of hydrophilic surfactants can include PEG-8 caprylic/capricglycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride,PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium laurylsulfate, sodium dioctyl sulfosuccinate, polyethylene glycol fatty acidsmono- and di-ester mixtures, polysorbate 80, polysorbate 20,polyethylene glycol 1000 tocopherol succinate, phytosterols, phytosterolfatty acid esters, and mixtures thereof.

In some embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include sterols and derivatives ofsterols. In various embodiments, these surfactants are hydrophilic orlipophilic. Examples of hydrophilic sterol surfactants are lanosterolPEG-24 cholesterol ether (e.g. Solulan C-24, Amerchol), PEG-30 soyasterol (e.g. Nikkol BPS-30, from Nikko), PEG-25 phyto sterol (e.g.Nikkol BPSH-25 from Nikko), PEG-30 cholestanol (e.g. Nikkol DHC, fromNikko). Examples of Lipophilic Sterol Surfactants are Cholesterol,sitosterol, Phytosterol (e.g. GENEROL series from Henkel), PEG-5 soyasterol (e.g. Nikkol BPS-S, from Nikko), PEG-10 soya sterol (e.g. NikkolBPS-10 from Nikko), PEG-20 soya sterol (e.g. Nikkol BPS-20 from Nikko).

In one embodiment, the pharmaceutical composition or unit dosage formincludes an additive as described in the following paragraphs.

Suitable additives utilized in various embodiments described hereininclude, by way of non-limiting example, adsorbing agents,anti-adherents, anticoagulants, antifoaming agents, antioxidants,anti-caking agents, anti-static agents, binders, bile acids, bufferants,bulking agents, chelating agents, coagulants, colorants, co-solvent,opaquants, congealing agents, coolants, cryoprotectants, diluents,dehumidifying agents, desiccants, desensitizers, disintegrants,dispersing agents, enzyme inhibitors, glidants, fillers, hydratingagent, super disintegrants, gums, mucilages, hydrogen bonding agents,enzymes, flavorants, humectants, humidifying agents, lubricant oils,ion-exchange resins, lubricants, plasticizers, pH modifying agents,preservatives, solidifying agent, solvents, solubilizers, spreadingagent sweeteners, stabilizers, surface area enhancing agents, suspendingagent, thickeners, viscosity increasing agents, waxes and mixturesthereof.

Some non-limiting examples of the additives suitable for the presentdisclosure may be: alcohols and/or polyols (e.g., ethanol, isopropanol,butanol, benzyl alcohol, ethylene glycol, propylene glycol, glycerol,sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, fatty acidalcohol, vinyl alcohol polypropylene glycol, polyvinylalcohol,tocopherols, cellulose cyclodextrins, other derivatives, forms, mixturesthereof, or the like); ethers of polyethylene glycols having an averagemolecular weight of about 200 to about 20,000 (e.g., tetrahydrofurfurylalcohol PEG ether, methoxy PEG, or the like); amides (e.g.,2-pyrrolidone, 2-piperidone, 8-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide, polyvinylpyrrolidone and the like.); esters (e.g.,ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyltributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethylbutyrate, triacetin, propylene glycol monoacetate, propylene glycoldiacetate, 8-caprolactone and isomers thereof, 6-valerolactone andisomers thereof, gamma-butyrolactone and isomers thereof; and otheradditives known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, or the like); amino acids (e.g., p-aminobenzamidine,sodium glycocholate) mesylate; amino acids and modified amino acids(e.g., aminoboronic acid derivatives and n-acetylcysteine; peptides andmodified peptides (e.g., bacitracin, phosphinic acid dipeptidederivatives, pepstatin, antipain, leupeptin, chymostatin, elastin,bestatin, phoshporamindon, puromycin, cytochalasin potatocarboxypeptidase inhibitor, amastatin, or the like); polypeptide proteaseinhibitors; mucoadhesive polymers (e.g., polyacrylate derivatives,chitosan, cellulosics, chitosan-EDTA, chitosan-EDTA-antipain,polyacrylic acid, carboxymethyl cellulose etc.) or the like; orcombinations thereof.

Some more examples of suitable additives for compositions and/or dosageforms described herein include, by way of non-limiting example, talc,magnesium stearate, silica (e.g., fumed silica, micronized silica,magnesium aluminum silicate etc.) and/or derivatives, polyethyleneglycols, surfactants, waxes, oils, cetyl alcohol, polyvinyl alcohol,stearic acid, stearic acid salts, stearic acid derivatives, starch,hydrogenated vegetable oils, hydrogenated castor oils, sodium benzoate,sodium acetate, leucine, PEG, alkyl sulfate salts; acetylatedmonoglycerides; long-chain alcohols; silicone derivatives; butylatedhydroxy toluene (BHT), butylated hydroxyl anisole (BHA), gallic acid,propyl gallate, ascorbic acid, ascorbyl palmitate,4-hydroxymethyl-2,6-di-tert-butyl phenol, dry starch, dry sugars,polyvinyl pyrrolidones, starch paste, methacrylic copolymers, bentonite,sucrose, polymeric cellulose derivatives, shellac, sugar syrup; cornsyrup; polysaccharides, acacia, tragacanth, guar gum, xanthan gums;alginates; gelatin; gelatin hydrolysate; agar; sucrose; dextrose; PEG,vinyl pyrrolidone copolymers, poloxamers; pregelatinized starch,sorbitol, glucose); acetic acid, hydrochloric acid, hydrobromic acid,hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid,acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid and uric acid, vinegar,pharmaceutically acceptable bases, such as an amino acid, an amino acidester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodiumhydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesiumhydroxide, magnesium aluminum silicate, synthetic aluminum silicate,synthetic hydrotalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamin; salt of a pharmaceutically acceptablecation and an anion; EDTA and EDTA salts; titanium dioxide, food dyes,lakes, natural vegetable colorants, iron oxides, silicates, sulfates,magnesium hydroxide and aluminum hydroxide; halogenated hydrocarbons,trichloroethane, trichloroethylene, dichloromethane,fluorotrichloromethane, diethylether, trehalose, phosphates, citricacid, tartaric acid, gelatin, dextran and mannitol, lactose, mannitol,sodium chloride, potassium chloride, spray-dried lactose, hydrolyzedstarches, directly compressible starch, microcrystalline cellulose,cellulosic derivatives, sorbitol, sucrose, sucrose-based materials,calcium sulfate, dibasic calcium phosphate, dextrose, croscarmellosesodium, starch, starch derivatives, clays, gums, cellulose, cellulosederivatives, alginates, crosslinked polyvinylpyrrolidone, sodium starchglycolate and microcrystalline cellulose, magnesium oxide, magnesiumcarbonates; desensitizers, spray-dried flavors, essential oils, ethylvanillin, styrene/divinyl benzene copolymers, quaternary ammoniumcompounds, polyethylene glycol, citrate esters (such as triethylcitrate, acetyl triethyl citrate, acetyltributyl citrate), acetylatedmonoglycerides, glycerin, triacetin, propylene glycol, phthalate esters(e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol anddibutyl sebacate, ascorbic acid, boric acid, sorbic acid, benzoic acid,and salts thereof, parabens, phenols, benzyl alcohol, and quaternaryammonium compounds; alcohols, ketones, esters, chlorinated hydrocarbonswater; sweeteners (e.g., maltose, sucrose, glucose, sorbitol, glycerinand dextrins, aspartame, saccharine, saccharine salts, glycyrrhizin),viscosity modifiers, sugars, polyvinylpyrrolidone, cellulosics,polymers, gums and/or alginates.

In one embodiment, additives may also be materials such as proteins(e.g., collagen, gelatin, Zein, gluten, mussel protein, lipoprotein);carbohydrates (e.g., alginates, carrageenan, cellulose derivatives,pectin, starch, chitosan); gums (e.g., xanthan gum, gum Arabic);spermaceti; natural or synthetic waxes; carnauba wax; fatty acids (e.g.,stearic acid, hydroxystearic acid); fatty alcohols; sugars; shellacs,such as those based on sugars (e.g., lactose, sucrose, dextrose) orstarches; polysaccharide-based shellacs (e.g., maltodextrin andmaltodextrin derivatives, dextrates, cyclodextrin and cyclodextrinderivatives); cellulosic-based polymers (e.g., ethyl cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethyl cellulose,hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropyl cellulose,HPMC acid succinates, cellulose acetate, cellulose nitrate, celluloseacetate butyrate, cellulose acetate trimellitate, carboxymethylethylcellulose, hydroxypropylmethyl cellulose phthalate), shellacs;inorganics, such as dicalcium phosphate, hydroxyapatite, tricalciumphosphate, talc and titania; polyols, such as mannitol, xylitol andsorbitol; polyethylene glycol esters; and polymers, such as alginates,poly(lactide coglycolide), gelatin, crosslinked gelatin, and agar-agar.Non-limiting examples of compounds (e.g., additives) that can be used asat least a part of the pharmaceutically acceptable carrier includewithout limitation celluloses; dextrins, gums, carbomers, methacrylates,sugars, lactoses, inorganic carbonates, oxides, chlorides, sulphates andthe like; salts of calcium; salts of magnesium; salts of fatty acids;inorganic and organic acids, bases and salts; propylene glycol;glycerols; fatty acids; fatty alcohols; fatty acid esters; glycerolesters; mono-, di- or triglycerides; edible oils; omega oils; vegetableoils, hydrogenated vegetable oils; partially or fully hydrogenatedvegetable oils; glycerol esters of fatty acids; waxes; alcohols;gelatin; polyethylene glycol; polyethylene oxide co-polymers; silicates;antioxidants, tocopherols, sugar stearates, starches, shellac, resins,proteins, acrylates; methyl copolymers; polyvinyl alcohol; starch;phthalates; and combinations thereof.

In one embodiment, the additive may include at least one componentselected from celluloses, dextrins, gums, carbomers, methacrylates,inorganic carbonates, salts of calcium, salts of magnesium, fatty acids,fatty acid esters, gelatin, lactoses, polyethylene glycol, polyethyleneoxide co-polymers, silicates, partially hydrogenated vegetable oils,fully hydrogenated vegetable oils, waxes, antioxidants, tocopherol,sugar stearates, starches, shellac, resins, proteins, and combinationsthereof.

In another embodiment, the additive may include at least one componentselected from celluloses, dextrins, gums, carbomers, methacrylates,sugars, lactoses, inorganic carbonates, salts of calcium, salts ofmagnesium, salts of fatty acids, inorganic and organic acids, bases andsalts, propylene glycol, glycerols, fatty acids, fatty alcohols, fattyacid esters, glycerol esters, mono-glycerol esters of fatty acids,di-glycerol esters of fatty acids, mixtures of mono-glycerol anddi-gylcerol esters of fatty acids, omega oils, waxes, alcohols, gelatin,polyethylene glycol, polyethylene oxide co-polymers, silicates,antioxidants, tocopherol, sugar stearates, starches, shellac, resins,proteins, acrylates, methyl copolymers, polyvinyl alcohol, starch,phthalates, and combinations thereof.

Non-limiting examples of additives as release modulators that may beused include lipophilic resins; ethyl cellulose (EC), methylethylcellulose (MEC), carboxymethyl ethylcellulose (CMEC), hydroxyethylcellulose (HEC), cellulose acetate (CA), cellulose propionate (CPr),cellulose butyrate (CB), cellulose acetate butyrate (CAB), celluloseacetate phthalate (CAP), cellulose acetate trimellitate (CAT),hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl celluloseacetate trimellitate (HPMCAT), ion-exchange resin; poloxamers; andethylhydroxy ethylcellulose (EHEC) tocopherol; shellac; and combinationsthereof. Non-limiting examples of lipidic lipophilic release modulatorsinclude fatty acids; mono-, di-, tri-esters of fatty acids withglycerol; sucrose esters with fatty acids; cetyl alcohol; stearic acid;glyceryl monostearate; glyceryl distearate; glyceryl tristearate;glyceryl palmitostearate; hydrogenated castor oil; butyl and glycolesters of fatty acids; oleic acid; cetyl alcohol; stearyl alcohol;cetostearyl alcohol; hydrogenated vegetable oil; waxes; bees wax; lard;omega fatty acid esters; hydrogenated soybean oil; hydrogenatedvegetable oil; hydrogenated cottonseed and castor oil; partiallyhydrogenated soybean oil; partially hydrogenated castor oil; partiallysoy and cottonseed oil; phospholipids; hydrogenated oils, and theirderivatives and combinations thereof.

In one embodiment, the oral pharmaceutical composition or the dosageform comprises or is prepared from solid (17-β)-3-Oxoandrost-4-en-17-yltridecanoate and a pharmaceutically acceptable carrier, wherein(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % toabout 75 wt %, about 5 wt % to about 50 wt %, about 10 wt % to about 40wt %, about 20 wt % to about 40 wt %, about 25 wt % to about 35 wt %, orabout 26% to about 32% of the composition or dosage form. In anotherembodiment, the compositions or the dosage form of the current inventionincludes solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and apharmaceutically acceptable carrier, wherein solid(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 5 wt % toabout 50 wt % of the composition or dosage form, and wherein the carrierincludes at least 50 wt % of the composition or the dosage form andwherein the solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is notsolubilized at 30° C., or above 30° C., or at a temperature range above30° C., including 30° C. to about 40° C. In an additional more specificembodiment, the solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is notfully dissolved in the carrier at human body temperature. In one aspect,the carrier includes a C16-C18 saturated fatty acid (or has 1, 2, or 3unsaturations), a mono-, di-, or triglyceride thereof (includingmixtures), or a combination thereof. In a more specific aspect, theC16-C18 fatty acid is stearic acid, oleic acid. In another specificaspect, the mono-, di-, or triglyceride is a glyceride of palmitic acid,stearic acid, oleic acid, linoleic acid or a combination thereof. Forexample, glyceryl palmitostearate. In one aspect, the pharmaceuticalcomposition or unit dosage forms comprises a PEG (e.g., from 200 to20000 average molecular weight). In one aspect, the pharmaceuticalcomposition or unit dosage forms comprises peppermint oil. In oneaspect, the pharmaceutical composition or unit dosage forms comprisesmenthol. In one aspect, the unit dosage form is a hard gel or soft gelcapsule or a tablet.

In another embodiment, the compositions or the dosage forms includes oris prepared from solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate EAPIand a pharmaceutically acceptable carrier, wherein the(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 5 wt % toabout 50 wt % of the composition or the dosage form, and wherein thecarrier includes about 50 wt % to about 100 wt % of lipophilicsurfactant and 0 wt % to about 50 wt % of hydrophilic surfactant. In oneaspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises %,about 20 wt % to about 40 wt %, about 25 wt % to about 35 wt %, or about26% to about 32% of the composition or dosage form. In a furtherembodiment, the ester is not solubilized at 30° C., or above 30° C., orat a temperature range above 30° C., including 30° C. to about 40° C. Inan additional more specific embodiment, the solid(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved inthe carrier at human body temperature. In one aspect, the carrierincludes a C16-C18 saturated fatty acid (or has 1, 2, or 3unsaturations), a mono-, di-, or triglyceride thereof (includingmixtures), or a combination thereof. In a more specific aspect, theC16-C18 fatty acid is stearic acid, oleic acid. In another specificaspect, the mono-, di-, or triglyceride is a glyceride of palmitic acid,stearic acid, oleic acid, linoleic acid or a combination thereof. Forexample, glyceryl palmitostearate. In one aspect, the pharmaceuticalcomposition or unit dosage forms comprises a PEG (e.g., from 200 to20000 average molecular weight). In one aspect, the pharmaceuticalcomposition or unit dosage forms comprises peppermint oil. In oneaspect, the pharmaceutical composition or unit dosage forms comprisesmenthol. In one aspect, the unit dosage form is a hard gel or soft gelcapsule or a tablet.

In another specific embodiment, the composition or the dosage formincludes or is prepared from solid (17-β)-3-Oxoandrost-4-en-17-yltridecanoate EAPI and a pharmaceutically acceptable carrier, wherein(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 5 wt % toabout 50 wt % of the composition or the dosage form, and the carrierincludes about 50 wt % to about 95 wt % a lipophilic surfactant and ahydrophilic surfactant 5 wt % to about 30 wt %. In one aspect, the(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises %, about 20 wt %to about 40 wt %, about 25 wt % to about 35 wt %, or about 26% to about32% of the composition or dosage form. In one aspect, the composition ordosage form comprises less than 25, 20, 15, 10, 8, 5, 4, 3, 2, or 1 wt %hydrophilic surfactant. In a further more specific embodiment, the EAPIis not solubilized at 30° C., or above 30° C., or at a temperature rangeabove 30° C., including 30° C. to about 40° C. In an additional morespecific embodiment, the EAPI is not fully dissolved in the carrier athuman body temperature. In another more specific embodiment, thecomposition or the dosage form can optionally contain about less than10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 wt % ethyl alcohol or has about 0 wt %.In one aspect, the carrier includes a C16-C18 saturated fatty acid (orhas 1, 2, or 3 unsaturations), a mono-, di-, or triglyceride thereof(including mixtures), or a combination thereof. In a more specificaspect, the C16-C18 fatty acid is stearic acid, oleic acid. In anotherspecific aspect, the mono-, di-, or triglyceride is a glyceride ofpalmitic acid, stearic acid, oleic acid, linoleic acid or a combinationthereof. For example, glyceryl palmitostearate. In one aspect, thepharmaceutical composition or unit dosage forms comprises a PEG (e.g.,from 200 to 20000 average molecular weight). In one aspect, thepharmaceutical composition or unit dosage forms comprises peppermintoil. In one aspect, the pharmaceutical composition or unit dosage formscomprises menthol. In one aspect, the unit dosage form is a hard gel orsoft gel capsule or a tablet.

In one embodiment, the hydrophilic surfactant can comprise at leastabout 20% of the total pharmaceutical carrier. In one aspect, the(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises %, about 20 wt %to about 40 wt %, about 25 wt % to about 35 wt %, or about 26% to about32% of the composition or dosage form. In another embodiment, thehydrophilic surfactant can comprise at least about 1, 2, 3, 4, 5, 10,15, or 20 wt % of the carrier. In another embodiment, the hydrophilicsurfactant can comprise less than 20, 15, 10, 6, 5, 4, 3, 2, or 1 wt %of the carrier or no hydrophilic surfactant is present in the carrier.In a related aspect, the hydrophilic surfactant can comprise at leastabout 20% of the total pharmaceutical composition (e.g., EAPI andcarrier). In another embodiment, the hydrophilic surfactant can compriseat least about 1, 2, 3, 4, 5, 10, 15, or 20 wt % of the pharmaceuticalcomposition. In another embodiment, the hydrophilic surfactant cancomprise less than 20, 15, 10, 6, 5, 4, 3, 2, or 1 wt % of thepharmaceutical composition or no hydrophilic surfactant is present. Inone aspect, the carrier includes a C16-C18 saturated fatty acid (or has1, 2, or 3 unsaturations), a mono-, di-, or triglyceride thereof(including mixtures), or a combination thereof. In a more specificaspect, the C16-C18 fatty acid is stearic acid or oleic acid. In anotherspecific aspect, the mono-, di-, or triglyceride is a glyceride ofpalmitic acid, stearic acid, oleic acid, linoleic acid or a combinationthereof. For example, glyceryl palmitostearate. In one aspect, thepharmaceutical composition or unit dosage forms comprises a PEG (e.g.,from 200 to 20000 average molecular weight). In one aspect, thepharmaceutical composition or unit dosage forms comprises peppermintoil. In one aspect, the pharmaceutical composition or unit dosage formscomprises menthol. In one aspect, the unit dosage form is a hard gel orsoft gel capsule or a tablet.

In another embodiment, the composition or the dosage form includes or isprepared from solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate EAPI,wherein the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises about5 wt % to about 50 wt % of the composition or the dosage form, andwherein the composition includes about 50 wt % to about 100 wt % oflipophilic additive and 0 wt % to about 50 wt % of hydrophilic additive.In one aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprisesabout 20 wt % to about 40 wt %, about 25 wt % to about 35 wt %, or about26% to about 32% of the composition or dosage form. In a specificembodiment, the lipophilic additive can be lipophilic surfactant and thehydrophilic additive can be hydrophilic surfactant. In a furtherembodiment, the ester is not solubilized at 30° C., or above 30° C., orat a temperature range above 30° C., including 30° C. to about 40° C. Inan additional more specific embodiment, the EAPI is not fully dissolvedin the lipophilic additive or the composition at human body temperature.In one aspect, the carrier includes a C16-C18 saturated fatty acid (orhas 1, 2, or 3 unsaturations), a mono-, di-, or triglyceride thereof(including mixtures), or a combination thereof. In a more specificaspect, the C16-C18 fatty acid is stearic acid or oleic acid. In anotherspecific aspect, the mono-, di-, or triglyceride is a glyceride ofpalmitic acid, stearic acid, oleic acid, linoleic acid or a combinationthereof. For example, glyceryl palmitostearate. In one aspect, thepharmaceutical composition or unit dosage forms comprises a PEG (e.g.,from 200 to 20000 average molecular weight). In one aspect, thepharmaceutical composition or unit dosage forms comprises peppermintoil. In one aspect, the pharmaceutical composition or unit dosage formscomprises menthol. In one aspect, the unit dosage form is a hard gel orsoft gel capsule or a tablet.

In some embodiments, the oral pharmaceutical composition or the dosageform can include both a lipophilic surfactant and hydrophilicsurfactant. In one aspect, the (17-β)-3-Oxoandrost-4-en-17-yltridecanoate comprises about 20 wt % to about 40 wt %, about 25 wt % toabout 35 wt %, or about 26 wt % to about 32 wt % of the composition ordosage form. In one embodiment, the lipophilic surfactant andhydrophilic surfactant can be present in amounts such that the ratio ofamount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilicsurfactant is greater than 2:1. In another embodiment, the lipophilicsurfactant and hydrophilic surfactant can be present in amounts suchthat the ratio of amount (wt %) of lipophilic surfactant to amount (wt%) of hydrophilic surfactant is greater than 2.5:1. In anotherembodiment, the lipophilic surfactant and hydrophilic surfactant can bepresent in amounts such that the ratio of amount (wt %) of lipophilicsurfactant to amount (wt %) of hydrophilic surfactant is greater than3.5:1. In still another embodiment, the lipophilic surfactant andhydrophilic surfactant can be present in amounts such that the ratio ofamount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilicsurfactant is at least 6.5:1.

Methods of Using Solid State EAPI and Products Derived Therefrom

In one embodiment, a pharmaceutical composition prepared by synthesizing(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate to produce crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate solid and mixing thecrystalline (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate with one or morepharmaceutically acceptable carriers to provide a pharmaceuticalcomposition which is substantially free of crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In a related embodiment, apharmaceutical composition is prepared by providing crystalline(17-β)-3-Oxoandrost-4-en-17 tridecanoate solid and mixing thecrystalline (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate with one or morepharmaceutically acceptable carriers to provide a pharmaceuticalcomposition which is substantially free of crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate.

Methods of Use

The solid state EAPI, pharmaceutical compositions comprising or preparedfrom the solid state EAPI, and unit dosage forms comprising or preparedthe solid state EAPI have a number of uses.

Subjects that can be treated by pharmaceutical compositions and unitdosage forms of the present disclosure (e.g., prepared from orcomprising solid state (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate) canbe any mammal (e.g., a human male or female) in need thereof. Inparticular, in one embodiment, the human male may be at least 14 yearsof age. In another embodiment, the human male is an adult of at leastage 16, 18, or 20. In another embodiment, the human male is an adult fat least age 21, 23 or 25. In another embodiment, the human male is anadult of at least age 30. In a further embodiment, the subject can be anadult male of at least age 50. In yet a further embodiment, the subjectcan be an adult male of at least age 60. Subjects that can be treated bypharmaceutical compositions and unit dosage forms of the presentdisclosure (e.g., prepared from or comprising solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate) can be any human male inneed thereof. In particular, in one embodiment, the human female may beat least 14 years of age. In another embodiment, the human female is anadult of at least age 30. In a further embodiment, the subject can be anadult female of at least age 50. In a further embodiment, the subjectcan be an adult female who has deficient endogenous serum testosteronelevels. In a further embodiment, the subject can be an adult female whohas undergone unilateral or bilateral oophorectomy. In yet a furtherembodiment, the subject can be an adult female who has undergoneunilateral or bilateral oophorectomy. In yet another embodiment, thesubject can be a post-menopausal woman.

As discussed above, the present invention also provides for a method oftreating a human subject in need of testosterone therapy is provided.The method can include the steps of administering any of thepharmaceutical compositions or dosage forms (e.g., capsule or tablet)disclosed herein. The pharmaceutical compositions and the dosage formsof the present invention can be used to treat any condition associatedwith testosterone deficiency, including complete absence, of endogenoustestosterone in male or female subjects. Examples of conditionsassociated with testosterone deficiency that can be treated using thedosage forms e.g., capsule or tablet) and/or compositions of the presentinvention include, but are not limited to congenital or acquired primaryhypogonadism, hypogonadotropic hypogonadism, cryptorchidism, bilateraltorsion, orchitis, vanishing testis syndrome, orchidectomy,Klinefelter's syndrome, post castration, eunuchoidism, hypopituitarism,endocrine impotence, infertility due to spermatogenic disorders,impotence, male sexual dysfunction (MSD) including conditions such aspremature ejaculation, erectile dysfunction, decreased libido, and thelike, micropenis and constitutional delay, penile enlargement, appetitestimulation, testosterone deficiency associated with chemotherapy,testosterone deficiency associated with toxic damage from alcohol,testosterone deficiency associated with toxic damage from heavy metal,osteoporosis associated with androgen deficiency, and combinationsthereof.

Other conditions that can be treated by the compositions and dosageforms disclosed herein include idiopathic gonadotropin, LHRH deficiency,or pituitary hypothalamic injury from tumors, trauma, or radiation.Typically, these subjects have low serum testosterone levels but havegonadotropins in the normal or low range. In one embodiment, thecompositions or oral dosage forms may be used to stimulate puberty incarefully selected males with clearly delayed puberty not secondary to apathological disorder. In another embodiment, the compositions and oraldosage forms may be used in female-to-male transsexuals in order tomaintain or restore male physical and sexual characteristics includingbody muscle mass, muscle tone, bone density, body mass index (BMI),enhanced energy, motivation and endurance, restoring psychosexualactivity etc. In some embodiments, pharmaceutical compositions and unitdosage forms of the present disclosure (e.g., prepared from orcomprising solid state (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate) canbe useful in providing hormonal male contraception. In some embodiments,pharmaceutical compositions and unit dosage forms of the presentdisclosure (e.g., prepared from or comprising solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate) can be used to providetreatment of one or more symptoms associated with female sexualdysfunction, anorgasmia, osteoarthritis, hormonal male contraception.Additionally, pharmaceutical compositions and unit dosage forms of thepresent disclosure (e.g., prepared from or comprising solid stat(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate) can be used to treat and/orimprove the patient related outcomes including the quality of life andwellbeing of the subjects suffering from deficiency of endogenoustestosterone. In some embodiments, pharmaceutical compositions and unitdosage forms of the present disclosure (e.g., prepared from orcomprising solid state 17-β)-3-Oxoandrost-4-en-17-yl tridecanoate) canbe used to treat or improve the symptoms of subjects suffering fromconditions such as decreased libido, diminishing memory, anemia due tomarrow failure, renal failure, chronic respiratory or cardiac failure,steroid-dependent autoimmune disease, muscle wasting associated withvarious diseases such as AIDS, preventing attacks of hereditaryangioedema or urticaria; andropause, and palliating terminal breastcancer. In some situations, certain biomarkers such as for example,increased SHBG levels, can be used to diagnose a subject who may be inneed of testosterone therapy. These biomarkers can be associated withconditions/disease states such as anorexia nervosa, hyperthyroidism,hypogonadism, androgen insensitivity/deficiency, alcoholic hepaticcirrhosis, primary biliary cirrhosis, and the like.

It has been discovered that pharmaceutical compositions (or unit dosageforms) prepared from or comprising specific solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate have a unique daily doserange for which, upon daily administration to each subject in a group(e.g., of at least for example 12 hypogonadal males) for a period of atleast 84 days, provides a serum testosterone C_(avg) of 300 ng/dL to1100 ng/dL in at least 75% of the hypogonadal males in the group, and atleast one of the following:

-   -   a steady state serum T concentration of <300 ng/dL for no more        than 7 hours in a 24-hour period in 50% or less of the subjects.    -   a steady state serum T concentration of >300 ng/dL for at least        12-24 hours post-dosing in a 24-hour period in majority of the        subjects.    -   a steady state serum T concentration serum T levels of <300        ng/dL for no more than 7 hours in a 24-hour period in 50% or        less subjects, 300 ng/dL for at least 12-24 hours post-dosing in        a 24-hour period in majority of the subjects.    -   a serum testosterone C_(max) of less than 1500 ng/dL in at least        85% of the subjects in the group;    -   a serum testosterone C_(max) of about 1800 ng/dL to about 2500        ng/dL in 5% or less of the subjects in the group; and    -   a serum testosterone C_(max) greater than 2500 ng/dL in about 1%        or less of the subjects in the group.

Contrary to expectations based on teachings in the art, it has beenfound that compositions prepared from or comprising solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate have unexpected lowersolubility in most of the commonly desired lipid solvents for(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate oral compositions. Given itsunique effective daily dose range it presents a challenge to designcompositions leading to patient-friendly dosage form and dosing regimen.It has been found that oral compositions prepared from or comprisingsolid state (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate need not bedissolved under ambient conditions or at human body temperature, besolubilized or be in solution (e.g. at or above 30° C., or at 30° C. to40° C. etc.) to provide the mean serum T C_(avg t12-t24) within thedesirable effective eugonadal range upon single oral administration,such that serum T levels are sustained in most of the patients atlevels >300 ng/dL for a large percentage of the dosing period with apatient-friendly regimen with lower dosing frequency administration in aday and/or with fewer number of dosage units per administration.

Accordingly, it has been discovered that by having a significant notdissolved or not solubilized fraction comprising solid state(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate dose in the composition ordosage form, one can achieve a practical dosing regimen with adequatedrug loading in the composition/dosage form that allows for adequatebioavailable testosterone levels restoration with manageable dosageunits per dose and thus, an oral therapy for treatment of hypogonadismthat is convenient, safe (e.g., C_(max) no more than 1500 ng/dL),effective (e.g., mean C_(avg t0-t24) within the eugonadal range of 300ng/dL to 1100 ng/dL), and longer lasting (e.g., mean serum TC_(avg t12-t24) at greater than 300 ng/dL upon a single administration).

The compositions and unit dosage forms can be prepared by any suitablemethod known to the skilled artisan or developed in view of theteachings herein.

In one specific aspect, the carrier(s) and API are brought to ormaintained at a temperature at which they are flowable (e.g., above 10°C., 20° C., 25° C., 30° C., 35° C., or 40° C.). In one aspect, themixture of carrier and API is a clear solution at a specifiedtemperature (e.g., above 10° C., 20° C., 25° C., 30° C., 35° C., or 40°C.). In one aspect, the mixture of carrier and API is a cloudy or hazysolution at a specified temperature (e.g., below 10° C., 20° C., 25° C.,30° C., 35° C., or 40° C.).

In one example, the composition is prepared by weighing all of thecomponents, except the API into a clean stainless steel container andmixed together at ambient temperature or at elevated temperatures e.g.,at about 25° C. to about 30° C., at about 30° C. to about 35° C., atabout 35° C. to about 40° C., at about 40° C. to about 45° C., at about45° C. to about 45° C., or 50° C. to about 70° C., using a stirrer. TheAPI is added and stirred into the mixture of other components until theAPI dissolves. A predetermined quantity of this “liquid fill material”is disposed into a capsule (for example, hard gelatin capsule) to getthe required API dose per dosage unit. The capsules are allowed to coolat room temperature, banded (if required) and packaged in a HDPE bottleand tightly closed with an appropriate lid. It is noted that variouscapsule sizes (e.g., hard gel or soft gel) are available to the skilledartisan and allow for variations in the amount of loading of API in mgper unit dosage form. Typically, soft gel capsules for oraladministration have fill volumes of less than 1.5 mL, 1.3 mL or 1.25 mLwith numerous incremental fill volumes in these ranges. Similarly, hardgel capsules typically have fill volumes of less than 1.25 mL, 1.10 mLor 1 mL. Due to the nature of some hard gel capsules, the total fillvolume may not be useable. There is a practical limit on the temperatureat which capsules can be filled—for example temperature above 40° C.typically melt, deform, or otherwise damage soft gel capsules typicallyemployed in the industry. Hard gel capsules are typically less sensitiveto temperature and can be filled at higher temperatures e.g., above 40°C.

In certain embodiments, any pharmaceutical composition described herein,e.g., a can be prepared by (i) combining and heating all ingredientsuntil a molten mixture is obtained (e.g., 50-70° C.); and (ii)encapsulating an amount of molten mixture comprising a select dose(e.g., a therapeutically effective amount or a partial dose of atherapeutically effective amount) API to obtain an oral dosage form. Incertain instances, the molten mixture is spray-congealed to obtainbeads. In some instances, the molten mixture is sprayed onto inert cores(e.g., sugar spheres) to obtain coated cores. In certain embodiments,such beads, cores, or similar forms are encapsulated or otherwiseformulated to provide an oral dosage form. In some instances, the moltenmixture is admixed, uniformly dispersed, or granulated over a carrierand compressed into a tablet dosage form. In certain embodiments, priorto compression, the molten mixture/carrier composition is further mixedwith one or more pharmaceutical aid including, by way of non-limitingexample, glidants, lubricants, binders, or the like. In someembodiments, the carrier is a therapeutically inert carrier such as, byway of non-limiting example, microcrystalline cellulose, starch,lactose, or the like.

In various embodiments, pharmaceutical compositions described herein areformulated as oral dosage forms. Oral dosage forms are prepared by anysuitable process including one or more steps of, by way of non-limitingexample, agglomeration, air suspension chilling, air suspension drying,balling, coacervation, comminution, compression, pelletization,cryopelletization, encapsulation, extrusion, granulation,homogenization, inclusion complexation, lyophilization,nanoencapsulation, melting, mixing, molding, pan coating, solventdehydration, sonication, spheronization, spray chilling, spraycongealing, spray drying, or the like.

In some embodiments, a pharmaceutical composition described herein isformulated with a substrate to form an oral dosage form. In variousembodiments, substrates useful for formulating pharmaceuticalcompositions described herein as oral dosage forms include or comprise,by way of non-limiting example, a powder or a multiparticulate (e.g.,one or more granule, one or more pellet, one or more bead, one or morespherule, one or more beadlet, one or more microcapsule, one or moremillisphere, one or more mini capsule, one or more microcapsule, one ormore nanocapsule, one or more nanosphere, one or more microsphere, oneor more minitablet, one or more tablet, one or more capsule, or one ormore combinations thereof). In certain instances, a powder constitutes afinely divided (milled, micronized, nanosized, precipitated) form of anactive ingredient or additive molecular aggregates or a compoundaggregate of multiple components or a physical mixture of aggregates ofan active ingredient and/or additives.

The following examples are provided to promote a more clearunderstanding of certain embodiments of this disclosure and are in noway meant as a limitation thereon.

EXAMPLE 1 Preparation of Solid State EAPI

A non-limiting exemplary synthetic scheme for producing a solid stateester of active pharmaceutical ingredient (EAPI) as disclosed herein isshown in FIG. 1A and is outlined in more detail below. The EAPI can beproduced utilizing the generalized scheme set forth below:

1) (17-β)-Hydroxy-4-Androsten-3-one (0.1 mol) is weighed into a 1000 mL4N RB flask containing a stir bar.

2) Pyridine (160 mL) is added to the flask.

3) The flask is placed in an ice-water bath and fitted with a nitrogeninlet, addition funnel, thermocouple, and stopper. Stirring and nitrogenflow are started.

4) The funnel is charged with a solution of acid chloride (1.56 equive.g., acid chloride of tridecanoic acid) in heptane (160 mL), thenfitted with an adapter connected to a bubbler.

5) The contents of the funnel are added dropwise over 30-40 min (Note:the internal temperature increases 5-7° C. during the addition.)

6) When the addition is complete, the bath is removed and stirring iscontinued.

7) After 1 h, the reaction mixture is transferred to a large separatoryfunnel and diluted with heptane (1000 mL) (Note: TLC at 1 h indicates acomplete reaction).

8) The heptane solution is washed successively with 800 mL portions of:cold water (2×), 0.05 N NaOH, saturated NaHC0₃ (2×), water, brine, thendried over anhydrous Na₂S0₄ (−50 g). Then concentrated to dryness(rotavap/Tbath:S; 30° C.).

EXAMPLE 2 Preparation of Solid State EAPI Crystals

A reaction mixture or product of Example 1 (or material produce byanother route) can be transferred to water, ethanol, or methanol (or anyother appropriate solvent) and allowed to crystallize. The crystallinemass can be filtered by suction, washed with water, dried overphosphorous pentoxide and re-crystallized from another solvent (althoughthis step is not necessary) e.g., oleic acid, hexane, heptanes, etc. SeeFIG. 1B

EXAMPLE 3 Differential Scanning Calorimetry of Solid State EAPI

This example demonstrates that the solid state EAPI has a distinctmelting point as determined using a differential scanning calorimeter.5.9 mg of solid state EAPI (e.g., (17-β)-3-Oxoandrost-4-en-17-yltridecanoate) was placed in the chamber of a DSC instrument and washeated from 10 to 120° C. The result is shown in FIG. 2, which shows asingle peak at about 72.78° C. FIG. 3 shows the first cooling cycle witha single peak at about 47.79° C. The second heating run of this sampleis show in FIG. 4 which shows a single peak at about 71.77° C. FIG. 5shows the second cooling cycle with a single peak at about 46.46° C.

EXAMPLE 4 Differential Scanning Calorimetry of PharmaceuticalComposition Having a Solid State Ester of Active PharmaceuticalIngredient Composition

This example demonstrates that a pharmaceutical composition has adistinct melting point as determined using a differential scanningcalorimeter. 29.1 mg of a pharmaceutical composition having a solidstate EAPI (e.g., (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate) and oneor more pharmaceutically acceptable carriers was placed in the chamberof a DSC instrument and was heated from 10 to 120° C. The result isshown in FIG. 6, which shows a broad peak at 55.52° C. The first heatcycle was similar to the second heat cycle with no peak corresponding toAPI. The cooling cycles showed no peaks. The formulation used in thisExample was prepared from about 14.5% to about 17% solid state EAPI(e.g., about 15%); about 50% to 75% lipophilic carrier (e.g., about 63%corn glycerides); about 10% to 25% hydrophilic carrier (e.g., about15%-16% polyoxylated hydrogenated castor oil) and about 2% to 10%solidifying agent (e.g., about 6% PEG 8000).

TABLE 1 Solid state forms of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoateApparent Apparent % Dissolved Solubility in solubility in % Dissolved in8% Triton Lipophilic Lipohilic in 8% Triton X100 aqueous additiveadditive (Corn X100 aqueous media at RT at Solid (Oleic acid)glycerides, media at RT at 30 min relative form % w/w Maisine) 30 min toform A* A <0.5 <0.5 <0.001 100 B >0.5 >0.5 >0.001 >120C >0.5 >0.5 >0.001 >120 D >0.5 >0.5 >0.001 >120 *Form A is the formdescribed herein and characterized in the Examples by DSC and XRD.

EXAMPLE 5 Compositions and PK Studies Related to Solid State EAPI (e.g.,(17-β)-3-Oxoandrost-4-en-17-yl Tridecanoate)

Tables 1A, 1B and 1C show the typical components and their relativeproportions that can be utilized in the compositions of the presentinventions having the (17-β)-3-Oxoandrost-4-en-17 yl tridecanoate setforth above. Any suitable method for preparing the compositions anddosage forms described herein can be used. In some instances, thecompositions are prepared by heating one or more of the carriercomponents to an elevated temperature e.g., above ambient temperature(above 20° C., to about 30° C., from about 30° C. to about 35° C., fromabout 35° C. to about 40° C., from about 40° C. to about 45° C., fromabout 45° C. to about 50° C., from about 50° C. to about 60° C., fromabout 60° C. to about 70° C., or 70° C. or more) to produce a moltencarrier and the solid (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate EAPIis added to the molten carrier which together which is flowable (e.g.,can be processed to fill soft or hard gel capsules). The mixture of thecarrier and EAPI is then formed into a unit dosage form. Typically uponcooling, the composition is a solid, semi-solid, paste, jelly, jelly orthe like. In other aspects, the carrier can be liquid at about ambienttemperature. In this case the carrier may still be warmed or heated asdescribed above prior to the addition of solid EAPI. Both solid andliquid compositions (and intermediate forms e.g., semi-solid) at e.g.,ambient temperature (and dosage forms containing these compositions) arecontemplated.

TABLE 1A Composition (weight %) Composition No. Component 1 2(17-β)-3-Oxoandrost-4-en-17-yl 10-35 — tridecanoate Carrier 50-90 50-90Adjuvant* q.s. 100 q.s. 100 *Optional

TABLE 1B Carrier components for compositions 1 and 2 of Table 1 Carriercomponent (weight %) Composition No. Carrier component 3 4 5 6 7 8Lipophilic additive 100 — 5-95 100 — 5-95 [e.g. Triglyceride, lipophilicsurfactant, tocopherol derivative, etc.] Hydrophilic additive — 100 5-95— 100 5-95 [e.g. Hydrophilic surfactant,]

TABLE 1C Composition (weight %) Composition No. Component 9 10 11(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate 12-30 15-25 10-22 Lipophilicsurfactant (e.g., Glyceryl 55-80 50-80 55-80 monolinoleate) Hydrophilicsurfactant (polyoxyl  0-20  0-20  0-20 hydrogenated castor oil) Alcohol(e.g., ethanol) >10 0 <10 Triglyceride (e.g., castor oil) — — <50Adjuvant* q.s q.s. q.s.

TABLE 2 Dosage Forms of Compositions of Table 1B and Solid Forms ofTable 1 and Relative Release Performance these Dosage Forms. Compo-Solid form of % Release in 8% % sition (17-β)-3-Oxo- Triton Aqueous Bio-carrier androst-4-en-17- Media at RT in avail- of table yl tridecanoate30 min Relative abil- Dosage form 1B of table 1 to Dosage Form 1 ity 1(not preferred) 3 A (not preferred) — <1% 2 3 B or C or D >120 >1% 3(not preferred) 4 A (not preferred) 100 <1% 4 4 B or C or D >120 >1%

EXAMPLE 6 Methods of Use of Solid State EAPI of this InventionComparative Pharmacokinetic Study

Some of the dosage forms of compositions described herein comprising orprepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate wereadministered to human subjects as a single dose of the esters tosubjects. Serial blood samples were drawn at predetermined time (e.g.,t=0, 12, 24, etc.) and analyzed for testosterone concentration using avalidated HPLC-MS/MS analytical method. The C_(max), C_(avg t1-t2),T_(max) and AUC_(t1-t2) are calculated for testosterone in the serum ofthe subjects. Pharmacokinetic and statistical analyses are performed onthe data obtained from the subjects. The pharmacokinetic parameters aredefined as follows:

-   AUC_(t1-t2): The area under the serum concentration versus time    curve, from time t1 (in hours) to time t2 (in hours) measurable    concentration of the administered drug, as calculated by the linear    trapezoidal method. For e.g., AUC_(t1-t24) refers to the area under    the serum concentration versus time curve, from time 0 (zero) hours    to time 24 hours post-administration of dose.-   C_(max): The maximum measured serum concentration of the    administered drug.-   C_(avg t1-t2): The average serum concentration of testosterone    obtained by dividing the AUC_(t1-t2)/|t2-t1|, where in t is time    post-administration of dose expressed in hours.-   T_(max): The time (in hours) at which the maximum measured plasma    concentration of the administered drug is achieved.-   Mean: Average value of measured parameter of all individual    subjects.-   C_(avg t0-t24): The average serum concentration of testosterone    obtained by dividing the AUC t_(0-t24) value by 24. This represents    the average serum testosterone level over a period starting from    time 0 (zero) hours to time 24 hours post-administration of dose. It    should also be noted that C_(avg t0-t24) is also referred to as    simply “C_(avg)” in this invention.-   C_(avg t0-t12): The average serum concentration of testosterone    obtained by dividing the AUC t_(0-t12) value by 12. This represents    the average serum testosterone level over a period starting from    time 0 (zero) hours to time 24 hours post-administration of dose.-   C_(avg t12-t24): The average serum concentration of testosterone    obtained by dividing the AUC t_(12-t24) value by 12. This represents    the average serum testosterone level over the second half of the    24-hours post-administration of dose period; i.e., from a period    starting from time 12 hours to time 24 hours post-administration of    dose.    Some of the pharmacokinetic results for the compositions are    summarized in the Tables below.

TABLE 3 Starting Total mg % Responders T Equivalent Dose withC_(ave t0-t24) % Responders with C_(max) (±dose adjustment in (ng/dL)(ng/dL) mg T equivalent)* 300-1140 ≦1500 1800-2500 >2500(17-β)-3-Oxoandrost-4-en- 300 (±50) QD 100 100 0-5 0-1 17-yltridecanoate (12-20%  350 (±100) BID 100 100 0-5 0-1 EAPI, 55-70%lipophilic 1000 (±200) QD or 100 0 20-30 60-80 additive (e.g.,lipophilic BID surfactant) Hydrophilic 100 (±50) QD or 50-65 100 0-5 0-1additive 12-20% (e.g. BID Hydrophilic surfactant))

TABLE 4 Composition No. 12 13 14 Composition (weight %) Components(17-β)-3-Oxoandrost-4-en-17-yl 10-30 10-30 10-30 tridecanoate Lipophilicadditive [e.g. surfactant 55-80 55-80 55-80 of HLB <10 such as mono- ordi- or tri- glyceride of fatty acid or fatty acid] Hydrophilic additive(e.g.  0-20  0-20  0-20 Surfactant with HLB >10 such as cremophor RH40)Adjuvant q.s. q.s q.s. Serum T pharmacokinetic results PK parameterDaily dose as mg T Equivalent 250-400 250-500 250-400 % of T-ester notdissolved in 0 >12 >40 lipophilic additive at body temperature % ofT-ester not dissolved in 0 >15 >50 lipophilic additive at 20° C. No. ofcapsules/daily T dose 4-5 3-7 1-3 Mean serum T C_(avg) _(t0-t24)/mg T1.65 1-2-2.2 1.86 equivalent [ng/dL/mg]

It is also notable that Compositions 12-14 can be formulated as acapsule or tablet dosage form. Further, each of the capsule dosage formscan be formulated to contain from about 50 mg to about 450 mg of theester (or more or less). For instance, the Compositions 12-14 can beformulated as a capsule or tablet dosage form.

Total daily ester dose administered is 300 to 1500 mg for Compositions12-14. Specifically, for Compositions 12-14 the total daily(17-β)-3-Oxoandrost-4-en-17-yl dose administered is from about 3000 mgto about 1500. However, it is notable that unlike Composition 12 thathas no “not dissolved” ester, Compositions 13 and 14 require fewerdosage units per administration.

Table 4 shows that the higher the fraction of the lipobalanced ester notdissolved or not solubilized, the fewer the number of daily dosage formunits (e.g., capsules) that need to be administered to achieve thedesirable serum testosterone levels when treating hypogonadism in a malewith (17-β)-3-oxoandrost-4-en-17-yl tridecanoate. It should be notedthat to provide the total daily dose of about 420 mg 850 mg of the(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate for a hypogonadal subject,no more than four oral dosage form units are required; even morepreferred is that no more than two oral dosage form units per day arerequired for administration.

Compositions 12-14 can be prepared with the lipophilic surfactant andhydrophilic surfactant in amounts such that the ratio of amount (wt %)of lipophilic surfactant to amount (wt %) of hydrophilic surfactant isgreater than 2:1. Specifically, the ratio of amount (wt %) of lipophilicsurfactant to amount (wt %) of hydrophilic surfactant can be greaterthan 2.5:1. Further, the ratio of amount (wt %) of lipophilic surfactantto amount (wt %) of hydrophilic surfactant can be greater than 3.5:1.Even further, the ratio of amount (wt %) of lipophilic surfactant toamount (wt %) of hydrophilic surfactant can be greater than 6.5:1.

Compositions 12-14 can be prepared with hydrophilic surfactant presentat 20 wt % or more of the total carrier. Compositions 12-14 can beprepared with hydrophilic surfactant present at 5 wt % or less of thetotal carrier. The lipophilic additives, the hydrophilic additives, andthe adjuvant for the representative inventive compositions shown inTable 7 can be similar to those described for compositions in Table 4.The pharmacokinetic (PK) evaluation procedure is given under Example 2.The PK results for the Compositions 13 and 14 or related capsule dosageforms thereof, following oral administration of single dose, twoconsecutive doses or steady state to a group of subjects, for example,hypogonadal males, along with a meal, are summarized in Table 5A, 5B and5C.

TABLE 5A Serum T pharmacokinetics for Compositions 13 and 14 followingsingle administration PK parameter Results Range of mean C_(max)/mg of Tequivalent dose, 1.4-4.5 [ng/dL/mg] Range of mean C_(avg t0-t24)/mg of Tequivalent dose, 1.2-2.2 [ng/dL/mg] Range of the C_(avg t12-t24) as % ofthe C_(avg t0-t24) 35-70 Duration of post-dosing time with serum Tat >300 12 to 24 hours ng/dL

TABLE 5B Serum T pharmacokinetics for Compositions 13 and 14 followingtwo consecutive dose administration PK parameter Results Time of Tconcentration below 300 ng/dL following 2 to 7 hours two consecutiveadministrations 24 hours apart (once daily) within 48 hour time periodTime of T concentration below 300 ng/dL following 0.5 to 3.5 hours twoconsecutive administrations about 12 hours apart (twice daily) within 24hours

TABLE 5C Steady state serum T pharmacokinetics for Compositions 13 and14 following at least 7 days continuous administration to a group of atleast 12 subjects PK parameter Results Time of T concentration below 300ng/dL following 3.5-6.5 hours once daily administration % of patientswith serum T <300 ng/dL for more <50% than 7 hours following once dailyadministration Time of T concentration below 300 ng/dL following 0.3 to3.5 hours twice daily administration % of patients with serum T <300ng/dL for more <20% than 7 hours following twice daily administration

It is noteworthy that unlike Composition 12, Compositions 13 and 14 arenot fully dissolved nor solubilized in the composition or dosage formthereof. Further, Compositions 13 and 14 provide, upon singleadministration with a meal to a human subject, a serum T meanC_(avg t0-t24)/mg of T equivalent dose administered in a range betweenthe 1.2 to 2.2 ng/dL/mg. Additionally, Compositions 13 and 14 enable apatient-friendly dosing regimen, for instance via fewer dosage units peradministration.

EXAMPLE 7 Dissolution Studies

The EAPI, compositions, dosage forms described herein containing(17-β)-3-oxoandrost-4-en-17-yl tridecanoate when subjected to in vitrodissolution testing using USP type 2 apparatus in about 1000 mL aqueousmedium, can shows a release profile such that amorphous or amorphouslike EAPI e.g., (17-β)-3-oxoandrost-4-en-17-yl tridecanoate releasesfaster than crystalline EAPI. The (17-β)-3-oxoandrost-4-en-17-yltridecanoate EAPI, pharmaceutical composition, or dosage form containingthe EAPI is subjected to in vitro dissolution testing using USP type 2apparatus in about e.g., 1000 mL 8% Triton X100 solution in water at aspecific temperature at 100 rpm for a specific time (e.g., 1, 2, 3, 4,5, 10, 15, 30, 45, 60, 75, 90, 120, 180, or 240 minutes).

EXAMPLE 8 XRD Studies

A sample of EAPI or comprising EAPI can be analyzed by XRD. According tothis example a sample of EAPI was analyzed by XRD using a Philips X′PertX-Ray Diffractometer (XRD). A sample (e.g., 75 mg) of EAPI preparede.g., by the method disclosed in Example 1 was deposited on a glassslide as a powder. A plot of the results obtained from this scan isshown in FIG. 6. The sample was scanned under the following conditions:

Scan Axis Gonio; Start Position [°2Th.] 2.0050; End Position [°2Th.]59.9950; Step Size [°2Th.] 0.0100; Scan Step Time [s] 0.5000; Scan TypeContinuous; Offset [°2Th.] 0.0000; Divergence Slit Type FixedMeasurement; Temperature [° C.] 25.00; Anode Material Cu; K-Alpha1 [Å]1.54060; K-Alpha2 [Å] 1.54443; K-Beta [Å] 1.39225; K-A2/K-A1 Ratio0.50000; Generator Settings 40 mA, 45 kV; Diffractometer Type0000000013083126; Diffractometer Number; Goniometer Radius [mm] 200.00;Incident Beam Monochromator No; and Spinning No.

EXAMPLE 9 Dissolution/Release Vs. Bioavailability

A clinical trial in humans was conducted with compositions made from orcomprising a solid state testosterone ester. Single dose pharmacokineticparameters were determined for the compositions in which the same mgamount of testosterone ester was dosed but the unit dosage forms haddifferent dissolution/release parameters. Thirty (30) minutes beforeadministration of each study formulation, subjects were served thefollowing standardized high-fat, high calorie breakfast, as recommendedin the U.S. Food and Drug Administration (FDA) guidance document“Food-Effect Bioavailability and Bioequivalence Studies. At least 10subjects were in each group. The subjects were healthy post-menopausalfemales 45 years of age or greater to minimize effects related toendogenous (17-β)-Hydroxy-4-Androsten-3-one.

(17-β)-Hydroxy-4-Androsten-3-one Ester Unit Dosage Form A set to normal:

-   AUC_(0-t)=1-   AUC_(0-∞)=1    (17-β)-Hydroxy-4-Androsten-3-one Ester Unit Dosage Form B:-   AUC_(0-t) normalized to Dosage Form A (B/A)=0.73-   AUC_(0-∞) normalized to Dosage Form A (B/A)=0.73    (17-β)-Hydroxy-4-Androsten-3-one Ester Unit Dosage Form C:-   AUC_(0-t) normalized to Dosage Form A (C/A)=0.46-   AUC_(0-∞) normalized to Dosage Form A (C/A)=0.46    (17-β)-Hydroxy-4-Androsten-3-one Ester Unit Dosage Form D:-   AUC_(0-t) normalized to Dosage Form A (D/A)=0.40-   AUC_(0-∞) normalized to Dosage Form A (D/A)=0.40    (17-β)-Hydroxy-4-Androsten-3-one Ester Formulation In Vitro Release    Profiles

Time to Time to Formulation Release 50% Release 90% Ester Unit DosageForm A 0.5 hours 1 hour Ester Unit Dosage Form B 1 hour 3 hours EsterUnit Dosage Form C 2 hours 5 hours Ester Unit Dosage Form D 5.5 hours 11hourThe release profiles were determined in a USP Type Apparatus at 37° C.at 100 rpm in Triton X100 8% in 1000 mL water.

EXAMPLE 10 Release Profile

The compositions, dosage forms described herein containing API cansubjected to in vitro dissolution (release) testing using USP type 2apparatus in about 1000 mL aqueous medium. The composition (e.g., dosageform) is subjected to in vitro dissolution testing using USP type 2apparatus in about e.g., 1000 mL 8% Triton X100 solution in water at aspecific temperature (e.g., 37° C.) at 100 rpm for a specific time(e.g., 1, 2, 3, 4, 5, 10, 15, 30, 45, 60, 75, 90, 120, 180, or 240minute time point where a sample is withdrawn and analyzed for APIcontent (e.g., via HPLC)).

EXAMPLE 11 Release Profile Stability

The compositions, dosage forms described herein containing API cansubjected to in vitro dissolution (release) testing using USP type 2apparatus in about 1000 mL aqueous medium as described in the aboveexample after storage for particular amounts of time under specificconditions. FIG. 7 shows the release profile stability of composition(B) composition (e.g., unit dosage form of composition (B) describedherein. The diamonds with solid line labeled 1 represents time point 0;the diamond with dotted line represents 1 month storage at 25° C. and60% relative humidity (labeled 2); the square with long dashed linerepresents 1 month storage at 40° C. and 75% relative humidity (labeled3); the square with dash dot line represents 3 month storage at 25° C.and 60% relative humidity (labeled 4); and the square with lighter solidline represents 3 month storage at 40° C. and 75% relative humidity(labeled 5). The X-axis represents time in hours with measurements madeat 15 min, 30 min, 45 min, 1 hour, 2 hours and 4 hours. The Y-axisrepresents percent API released in 1000 mL 8% Triton X-100 media at 37°C. with a USP Type 2 Apparatus at 100 RPM.

FIG. 8 shows the release profile stability for composition (A) at time 0(1), 1 month stored at either 25° C. 60% RH (2) or 40° C. 75% RH (3), 2months stored at either at either 25° C. 60% RH (4) or 40° C. 75% RH(5), and 3 months stored at either at either 25° C. 60% RH (6) or 40° C.75% RH (7). RH is relative humidity. The X-axis represents time in hourswith measurements made at 15 min, 30 min, 45 min, 1 hour, 2 hours, 3hours and 4 hours. The Y-axis represents percent API released in 1000 mL8% Triton X-100 media at 37° C. with a USP Type 2 Apparatus at 100 RPM.

Composition (A)

Weight Percent Quantity Fill Quantity Fill of Fill Material per Materialper Pharmaceutical Hard Gel Soft Gel Composition Capsule Capsule (±1%)(±1%) (±1%) Ingredient Name % w/w mg mg API 24 183 300 Oleic Acid, NF 41308 513 Peppermint Oil, 18 136 225 NF Polyoxyl 40 4 30 50 HydrogenatedCastor Oil, NF Ascorbyl 0.2 1.5 2.5 Palmitate, NF Glyceryl 12 90 150Palmitostearate (Glyceryl Distearate, NF) Total 100 750 1241Composition (B)

Weight Percent Quantity Fill Quantity Fill of Fill Material per Materialper Pharmaceutical Hard Gel Soft Gel Composition Capsule Capsule (±1%)(±1%) (±1%) Ingredient Name % w/w mg mg API 28 183 350 Oleic Acid, NF 55365 688 Polyoxyl 40 4 26 50 Hydrogenated Castor Oil, NF Stearic Acid, NF4 26 50 Glyceryl 8 52 100 Palmitostearate (Glyceryl Distearate, NF;Precirol ATO 5) Ascorbyl 0.2 1.3 2.5 Palmitate, NF Total 100 654 1241It is understood that the above-described various types of compositions,dosage forms and/or modes of applications are only illustrative ofpreferred embodiments of the present invention. Numerous modificationsand alternative arrangements may be devised by those skilled in the artwithout departing from the spirit and scope of the present invention andthe appended claims are intended to cover such modifications andarrangements. Thus, while the present invention has been described abovewith particularity and detail in connection with what is presentlydeemed to be the most practical and preferred embodiments of theinvention, it will be apparent to those of ordinary skill in the artthat variations including, but not limited to, variations in size,materials, shape, form, function and manner of operation, assembly anduse may be made without departing from the principles and concepts setforth herein.

What is claimed is:
 1. A pharmaceutical composition comprising orprepared from a crystalline (17-β)-3-Oxoandrost-4-en-17-yl tridecanoateform having a melting point in the range of 68-75° C. and apharmaceutically acceptable carrier.
 2. The pharmaceutical compositionof claim 1 comprising a crystalline (17-β)-3-Oxoandrost-4-en-17-yltridecanoate form having a melting point in the range of 68-75° C. 3.The pharmaceutical composition of claim 1 prepared from a crystalline(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate form having a melting pointin the range of 68-75° C.
 4. The pharmaceutical composition of claim 1wherein said pharmaceutically acceptable carrier comprises a lipophilicsurfactant.
 5. The pharmaceutical composition of claim 1 wherein saidpharmaceutically acceptable carrier comprises a hydrophilic surfactant.6. The pharmaceutical composition of claim 1 wherein saidpharmaceutically acceptable carrier comprises a fatty acid.
 7. Thepharmaceutical composition of claim 1 wherein said pharmaceuticallyacceptable carrier comprises a monoglyceride.
 8. The pharmaceuticalcomposition of claim 1 wherein said pharmaceutically acceptable carriercomprises a diglyceride.
 9. The pharmaceutical composition of claim 1wherein said pharmaceutically acceptable carrier comprises apolyethylene glycol.
 10. The pharmaceutical composition of claim 1formulated as a capsule or tablet.
 11. The pharmaceutical composition ofclaim 1 formulated for oral administration.
 12. The pharmaceuticalcomposition of claim 1 crystalline (17-β)-3-Oxoandrost-4-en-17-yltridecanoate form having a melting point in the range of 69-73° C. 13.The pharmaceutical composition of claim 1 when tested with a USP type 2apparatus in about 1000 mL 8% Octoxynol-9 solution in water at 37° C.(±0.5)) at 100 rpm releases at least 40% of the(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate at 60 minutes.
 14. Thepharmaceutical composition of claim 1 that releases greater than 70% ofthe (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate at 2 hours when testedwith a USP type 2 apparatus in about 1000 mL 8% Octoxynol-9 solution inwater at 37° C. (±0.5)) at 100 rpm.
 15. The pharmaceutical compositionof claim 1 that releases less than 100% of the(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate at 30 minutes when tested ina USP type 2 apparatus in about 1000 mL 8% Octoxynol-9 solution in waterat 37° C. (±0.5)) at 100 rpm.
 16. The pharmaceutical composition ofclaim 1 that releases greater than 70% of the(17-β)-3-Oxoandrost-4-en-17-yl tridecanoate at 2 hours and less than100% at 30 minutes when tested with a USP type 2 apparatus in about 1000mL 8% Octoxynol-9 solution in water at 37° C. (±0.5)) at 100 rpm. 17.The pharmaceutical composition of claim 1 having from about 200 mg toabout 300 mg (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate.
 18. Thepharmaceutical composition of claim 1 wherein said pharmaceuticallyacceptable carrier comprises a polyethylene glycol having an averagemolecular weight of about 8000 grams per mole (PEG 8000).